BIRC5

Gene Summary

Gene:BIRC5; baculoviral IAP repeat containing 5
Aliases: API4, EPR-1
Location:17q25.3
Summary:This gene is a member of the inhibitor of apoptosis (IAP) gene family, which encode negative regulatory proteins that prevent apoptotic cell death. IAP family members usually contain multiple baculovirus IAP repeat (BIR) domains, but this gene encodes proteins with only a single BIR domain. The encoded proteins also lack a C-terminus RING finger domain. Gene expression is high during fetal development and in most tumors, yet low in adult tissues. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jun 2011]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:baculoviral IAP repeat-containing protein 5
Source:NCBIAccessed: 11 March, 2017

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (9)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Breast CancerBIRC5 and Breast Cancer View Publications329
Lung Cancer, Small CellSurvivin Expression in Colorectal Cancer View Publications283
Bladder CancerBIRC5 and Bladder Cancer View Publications150
Lung CancerSurvivin Expression in Non Small Lung Cancer
Researchers in Germany (Monzo, 1999) used RT-PCR to detect survivin gene transcripts in 83 NSCLC tumour samples and in paired normal lung tissues. The survivin gene transcript was found in 71 (86%) of the tumours and in only 10 (12%) of the normal lung samples. Moreover, the 12 patients without survivin expression were found to have significantly better survival than the 71 patients with survivin expression.
View Publications152
Skin CancerBIRC5 and Skin Cancer View Publications84
NeuroblastomaSurvivin Expression in Neuroblastoma View Publications63
Thyroid CancerBIRC5 and Thyroid Cancer View Publications27
Wilms TumourBIRC5 and Wilms Tumour View Publications5

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: BIRC5 (cancer-related)

Nitta T, Koike H, Miyao T, et al.
YM155 Reverses Statin Resistance in Renal Cancer by Reducing Expression of Survivin.
Anticancer Res. 2017; 37(1):75-80 [PubMed] Related Publications
AIM: The purpose of the present study was to clarify whether treatment with YM155, a novel small-molecule inhibitor of survivin, reverses statin resistance in statin-resistant renal cell cancer (RCC).
MATERIALS AND METHODS: We induced simvastatin resistance in a renal clear cell carcinoma cell line (Caki-1-staR). In vitro and in vivo models were used to test the efficacy of YM155 and simvastatin.
RESULTS: Survivin gene expression was significantly stronger in Caki-1-staR cells than in its parent cells (Caki-1). In Caki-1-staR cells, YM155 significantly reduced expression of survivin gene and cell proliferation in a dose-dependent manner. Treatment with YM155 significantly reversed simvastatin resistance in Caki-1-staR cells. YM155 significantly inhibited the growth of Caki-1-staR tumors in a nude mouse tumor xenograft model. Furthermore, YM155 significantly enhanced the antitumor effects of simvastatin on Caki-1-staR tumors.
CONCLUSION: Our results indicate that inhibition of survivin by YM155 overcomes statin resistance in RCC cells.

Stache C, Bils C, Fahlbusch R, et al.
Drug priming enhances radiosensitivity of adamantinomatous craniopharyngioma via downregulation of survivin.
Neurosurg Focus. 2016; 41(6):E14 [PubMed] Related Publications
OBJECTIVE In this study, the authors investigated the underlying mechanisms responsible for high tumor recurrence rates of adamantinomatous craniopharyngioma (ACP) after radiotherapy and developed new targeted treatment protocols to minimize recurrence. ACPs are characterized by the activation of the receptor tyrosine kinase epidermal growth factor receptor (EGFR), known to mediate radioresistance in various tumor entities. The impact of tyrosine kinase inhibitors (TKIs) gefitinib or CUDC-101 on radiation-induced cell death and associated regulation of survivin gene expression was evaluated. METHODS The hypothesis that activated EGFR promotes radioresistance in ACP was investigated in vitro using human primary cell cultures of ACP (n = 10). The effects of radiation (12 Gy) and combined radiochemotherapy on radiosensitivity were assessed via cell death analysis using flow cytometry. Changes in target gene expression were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Survivin, identified in qRT-PCR to be involved in radioresistance of ACP, was manipulated by small interfering RNA (siRNA), followed by proliferation and vitality assays to further clarify its role in ACP biology. Immunohistochemically, survivin expression was assessed in patient tumors used for primary cell cultures. RESULTS In primary human ACP cultures, activation of EGFR resulted in significantly reduced cell death levels after radiotherapy. Treatment with TKIs alone and in combination with radiotherapy increased cell death response remarkably, assessed by flow cytometry. CUDC-101 was significantly more effective than gefitinib. The authors identified regulation of survivin expression after therapeutic intervention as the underlying molecular mechanism of radioresistance in ACP. EGFR activation promoting ACP cell survival and proliferation in vitro is consistent with enhanced survivin gene expression shown by qRT-PCR. TKI treatment, as well as the combination with radiotherapy, reduced survivin levels in vitro. Accordingly, ACP showed reduced cell viability and proliferation after survivin downregulation by siRNA. CONCLUSIONS These results indicate an impact of EGFR signaling on radioresistance in ACP. Inhibition of EGFR activity by means of TKI treatment acts as a radiosensitizer on ACP tumor cells, leading to increased cell death. Additionally, the results emphasize the antiapoptotic and pro-proliferative role of survivin in ACP biology and its regulation by EGFR signaling. The suppression of survivin by treatment with TKI and combined radiotherapy represents a new promising treatment strategy that will be further assessed in in vivo models of ACP.

Rogers MA, Kalter V, Strowitzki M, et al.
IGF2 knockdown in two colorectal cancer cell lines decreases survival, adhesion and modulates survival-associated genes.
Tumour Biol. 2016; 37(9):12485-12495 [PubMed] Related Publications
Increased expression of insulin-like growth factor 2 (IGF2) is found in tumors of colorectal cancer (CRC) patients exhibiting a gained region on chromosome 11q15 and is implicated in poor patient survival. This study analyzes in vitro phenotypic- and gene expression changes associated with IGF2 shRNA-mediated knockdown. Initially, doxycycline inducible IGF2 knockdown cell lines were generated in the CRC cell lines SW480 and LS174T. The cells were analyzed for changes in proliferation, cell cycle, apoptosis, adhesion, and invasion. Expression profiling analysis was performed, and, for a subset of the identified genes, expression was validated by qRT-PCR and Western blot. IGF2 knockdown inhibited cell proliferation in both cell lines induced G1 cell cycle blockade and decreased adhesion to several extracellular matrix proteins. Knockdown of IGF2 did not alter invasiveness in SW480 cells, while a slight increase in apoptosis was seen only in the LS174T cell line. Knockdown of IGF2 in SW480 deregulated 58 genes, several of which were associated with proliferation and cell-cell/cell-ECM contacts. A subset of these genes, including CDK2, YAP1, and BIRC5 (Survivin), are members of a common network. This study supports the concept of direct autocrine/paracrine tumor cell activation through IGF2 and a shows role of IGF2 in CRC proliferation, adhesion and, to a limited extent, apoptosis.

Nooshinfar E, Bashash D, Safaroghli-Azar A, et al.
Melatonin promotes ATO-induced apoptosis in MCF-7 cells: Proposing novel therapeutic potential for breast cancer.
Biomed Pharmacother. 2016; 83:456-465 [PubMed] Related Publications
Arsenic trioxide (ATO), a traditional Chinese medicine, has long been of biomedical interest and is largely used for treatment of a broad spectrum of cancers. Melatonin, a naturally occurring indoleamine synthesized in the pineal gland, has been considered as a biomarker for endocrine-dependent tumors, particularly breast cancer. An increasing number of studies indicate that melatonin could be an attractive candidate for combined therapy due to its anti-oxidant and cytotoxic activities. The aim of this study was to investigate the potentiating effect of melatonin on ATO-induced apoptosis in estrogen receptor (ER)-positive breast cancer cell line, MCF-7. Our data highlighted for the first time that pre-treating MCF-7 cells with physiological concentration of melatonin substantially augmented the cytotoxic effects of ATO as compared with either agent alone. Real-time PCR analysis revealed that apoptosis induction by the drugs combination was associated with increased p53 transcriptional activity followed by the elevated molecular ratio of Bax/Bcl-2. Moreover, induced p21, subsequent G1 cell cycle arrest and transcriptional suppression of survivin-mediated c-Myc and hTERT expression may contribute in the enhanced growth suppressive effect of ATO-plus-melatonin. Due to the safety profile of melatonin, our study suggests that using melatonin in combination with ATO might provide insight into a novel adjuvant therapy and may confer advantages for breast cancer treatment.

Arami S, Mahdavi M, Rashidi MR, et al.
Novel polyacrylate-based cationic nanoparticles for survivin siRNA delivery combined with mitoxantrone for treatment of breast cancer.
Biologicals. 2016; 44(6):487-496 [PubMed] Related Publications
As a gene delivery method in breast cancer therapy, knocking down the undesired genes in the cancerous cells would be promising. Inhibitors of Apoptosis Protein (IAP) family genes are some of the genes whose responsibility is inhibition of apoptosis in cells. Silencing these genes seems to be helpful directing the tumor cells to death. siRNA sequence designed against survivin anti-apoptotic gene can play this role if carried to the cytoplasm. Here we prepared a positive charged biocompatible nano-sized particle made up of a Fe3O4 core covered respectively by polyacrylate (PA) and polyethyleneimine (PEI) layer, which could successfully deliver the siRNA into the MCF-7 cells. The particle structure was checked and having less than 50 nm diameter in size, positive charge and, safety towards MCF-7 cells besides being able to form nanoplexes with the siRNA strand helps it entering into the biologic assays part. The siRNA delivery evaluated via flowcytometry. Apoptosis induction was determined by DAPI staining. The efficiency of survivin gene knockdown was evaluated in mRNA and protein levels using Real time PCR and western blotting methods. Overall, the Fe3O4-PA-PEI nanoparticles can deliver siRNA effectively into the cytoplasm of the MCF-7 breast cancer cells and induce apoptosis.

Yin XZ, Zhao DM, Zhang GX, Liu L
Effect of miRNA-203 on cervical cancer cells and its underlying mechanism.
Genet Mol Res. 2016; 15(3) [PubMed] Related Publications
miRNA-203 is involved in the development and progression of various types of cancer. However, its role in cervical cancer remains unclear. The aim of this study was to investigate the effect of miRNA-203 on the proliferation and migration of HeLa cervical cancer cells, as well as survivin expression in these cells. A miRNA-203 primer probe was designed according to a sequence obtained from NCBI. The expression of miRNA-203 in cervical epithelial cells and cervical cancer cells was detected by quantitative reverse transcriptase-polymerase chain reaction. The miRNA-203 expression pattern was compared between these two cell lines. The cervical cancer cells were transfected with miRNA-203 mimic or inhibitor to determine their effects on proliferation and migration. The expression of the miRNA-203 target protein (survivin) was analyzed by western blot. Cervical cancer cells showed reduced miRNA-203 expression compared to cervical epithelial cells. Transfection of miRNA-203 mimic upregulated the expression of miRNA-203, suppressed cell proliferation and migration, and downregulated survivin expression (P < 0.05). However, downregulation of miRNA-203 expression did not affect proliferation, migration, and survivin expression in cervical cancer cells (P > 0.05). In conclusion, upregulation of miRNA-203 in cervical cancer cells inhibits the proliferative and migratory capacities of these cells by downregulating the expression of survivin.

Ma X, Zhang Y, Kang Y, et al.
A recombinant protein TmSm(T34A) can inhibit proliferation and proapoptosis to breast cancer stem cells(BCSCs) by down-regulating the expression of Cyclin D1.
Biomed Pharmacother. 2016; 84:373-381 [PubMed] Related Publications
Cancer stem cells (CSCs), a small fraction of cancer cells lines proved with stem cell characteristics, were regarded as "bad seeds" related to recurrence, metastasis and chemotherapy resistance of breast carcinoma in recent years. So inhibiting the growth or inducing the differentiation and apoptosis of CSCs were considered as one of the effective pathways to fight against breast cancer. Based on the recombinant protein TmSm(T34A) that was designed and prepared in our previous experiments for targeting survivin, an inhibitor of apoptosis protein(IAP), in this study, we explored the effects of TmSm(T34A) on BCSCs obtained by enriching in serum-free suspension, sorting and characterizing of MCF-7/ADM. The results showed that TmSm(T34A) could not only inhibit the proliferation and growth of BCSCs by decreasing CD44(+)CD24(-) proportion and down-regulating the expression of Cyclin D1 significantly, but also induce BCSCs apoptosis evidently. Furthermore, in BCSCs xenograft nude mice administrated TmSm(T34A), the tumor growth was slower than that of the control obviously. Thus it can be seen TmSm(T34A) would be a promising potential protein for treatment of breast cancer by effecting on BCSCs.

Zhang S, Wang X, Gu Z, Wang L
Small Molecule Survivin Inhibitor YM155 Displays Potent Activity Against Human Osteosarcoma Cells.
Cancer Invest. 2016; 34(8):401-7 [PubMed] Related Publications
Survivin is an important oncogenic protein expressed highly in osteosarcoma. Here, we have shown that small molecule inhibitor YM155 potently suppressed survivin expression, inhibited cell growth, and induced apoptosis in osteosarcoma cells. Furthermore, we also showed that knock down of survivin by small interfering RNA strongly inhibited cell viability in two osteosarcoma cell lines, suggesting that suppression of survivin essentially contributes to YM155-mediated anticancer activity in osteosarcoma cells. Collectively, our study suggests that YM155 holds promise for patients with osteosarcoma.

Kim TH, Chang JH, Lee HJ, et al.
mRNA expression of CDH3, IGF2BP3, and BIRC5 in biliary brush cytology specimens is a useful adjunctive tool of cytology for the diagnosis of malignant biliary stricture.
Medicine (Baltimore). 2016; 95(27):e4132 [PubMed] Free Access to Full Article Related Publications
Although advances have been made in diagnostic tools, the distinction between malignant and benign biliary strictures still remains challenging. Intraductal brush cytology is a convenient and safe method that is used for the diagnosis of biliary stricture, but, low sensitivity limits its usefulness. This study aimed to demonstrate the usefulness of mRNA expression levels of target genes in brush cytology specimens combined with cytology for the diagnosis of malignant biliary stricture. Immunohistochemistry for cadherin 3 (CDH3), p53, insulin-like growth factor II mRNA-binding protein 3 (IGF2BP3), homeobox B7 (HOXB7), and baculoviral inhibitor of apoptosis repeat containing 5 (BIRC5) was performed in 4 benign and 4 malignant bile duct tissues. Through endoscopic or interventional radiologic procedures, brush cytology specimens were prospectively obtained in 21 and 35 paitents with biliary strictures. In the brush cytology specimens, the mRNA expressions levels of 5 genes were determined by real-time polymerase chain reaction. Immunohistochemistry for CDH3, p53, IGF2BP3, HOXB7, and BIRC5 all showed positive staining in malignant tissues in contrast to benign tissues, which were negative. In the brush cytology specimens, the mRNA expression levels of CDH3, IGF2BP3, HOXB7, and BIRC5 were significantly higher in cases of malignant biliary stricture compared with cases of benign stricture (P = 0.006, P < 0.001, P < 0.001, and P = 0.001). The receiver-operating characteristic curves of these 4 mRNAs demonstrated that mRNA expression levels are useful for the prediction of malignant biliary stricture (P = 0.006, P < 0.001, P < 0.001, and P = 0.002). The sensitivity and specificity, respectively, for malignant biliary stricture were 57.1% and 100% for cytology, 57.1% and 64.3% for CDH3, 76.2% and 100% for IGF2BP3, 71.4% and 57.1% for HOXB7, and 76.2% and 64.3% for BIRC5. When cytology was combined with the mRNA levels of CDH3, IGF2BP3, or BIRC5, the sensitivity for malignant biliary stricture improved to 90.5%. The measurement of the mRNA expression levels of CDH3, IGF2BP3, and BIRC5 by real-time polymerase chain reaction combined with cytology was useful for the differentiation of malignant and benign biliary strictures in brush cytology specimens.

Zhao G, Ge T, Yang X, Li X
The direct anti-cancer efficacy of Sapylin on breast cancer cells in vitro and in vivo.
Hell J Nucl Med. 2016 May-Aug; 19(2):111-7 [PubMed] Related Publications
OBJECTIVE: On the basis of our previous study in which we studied cancer cells under in vitro and in vivo hypoxia conditions, we have now investigated the anti-cancer efficacy of Sapylin on breast cancer cells in mice and human.
MATERIALS AND METHODS: We used different concentrations of Sapylin and the three kinds of breast cancer cells. We used water-soluble tetrazolium salt cell proliferation test (WST-1) to detect changes in cell proliferation and Fluorescein Iothiocyanate-Propidium Iodide (Anexin V FITC-PI) to detect changes in the rate of apoptosis by flow cytometry. We also used reverse transcription-polymerase chain reaction (RT-PCR) to detect possible changes of mRNA expression and used western blot in order to test changes related to protein expression that could lead to cell death. The anti-tumor effect was studied by locally injecting Sapylin into an animal tumor model of breast cancer. We also studied the possible postoperative adverse clinical side effects in 60 female breast cancer patients, stage II-III, aged 25-55 years. The patients underwent a modified, radical operation with smooth incisions which healed well.
RESULTS: Sapylin was able to inhibit by 10%-15% the proliferation of all three kinds of breast cancer cells and also to present positive correlation in vivo with some phenomenona which were time and concentration dependent. After applying Sapylin for 48h, the apoptosis rate was significantly increased by 12%-20%. Apoptosis of breast cancer cells may be related to biological effects supporting cells survival, through B-cell lymphoma gene 2 (Bcl-2nd) Ki67 mRNA expression descent and Bcl-2 associated X Protein (Bax mRNA) expression. This process ultimately promotes cell death. At the same time this process also showed a significant anti-tumor effect (50%-60%) in a mice model. We found no significant adverse reactions, the patients had no significant pain and the postoperative wound was partially healed. After 5 days, the drainage was well reduced and remained so more in the study group than in the control group at a range of 20%-30% (P<0.05).
CONCLUSION: In our research, Sapylin displayed a strong direct anti-cancer effect in breast cancer cells and supported postoperative recovery. Clinically we noticed an obvious reduction of drainage in contrast with the control group.

Zhang W, Liu Y, Li YF, et al.
Targeting of Survivin Pathways by YM155 Inhibits Cell Death and Invasion in Oral Squamous Cell Carcinoma Cells.
Cell Physiol Biochem. 2016; 38(6):2426-37 [PubMed] Related Publications
BACKGROUND/AIMS: Specific overexpression in cancer cells and evidence of oncogenic functions make Survivin an attractive target in cancer therapy. The small molecule compound YM155 has been described as the first "Survivin suppressant" but molecular mechanisms involved in its biological activity and its clinical potential remain obscure. Survivin protein plays critical roles in oral squamous cell carcinoma (OSCC), suggesting that YM155 would be extremely valuable for OSCC. In this study, we tested our hypothesis whether YM155 could be an effective inhibitor of cell growth, invasion and angiogenesis in oral squamous cell carcinoma (OSCC) cells.
METHODS: SCC9 and SCC25 were treated with different concentration of YM155 for indicated time. Using MTT assay and flow cytometry analysis to detect cell growth and apoptosis; Using transwell and Wound healing assay to detect migration and invasion; Using reverse transcription-PCR, Western blotting and electrophoretic mobility shift assay for measuring gene and protein expression, and DNA binding activity of NF-x03BA;B.
RESULTS: YM155 inhibited survivin-rich expressed SCC9 cell growth in a dose- and time dependent manner. This was accompanied by increased apoptosis and concomitant attenuation of NF-x03BA;B and downregulation of NF-x03BA;B downstream genes MMP-9, resulting in the inhibition of SCC9 cell migration and invasion in vitro and caused antitumor activity and anti metastasis in vivo. YM155 treatment did not affect cell growth, apoptosis and invasion of surviving-poor expressed SCC25 cells in vitro.
CONCLUSIONS: YM155 is a potent inhibitor of progression of SCC9 cells, which could be due to attenuation of survivin signaling processes. Our findings provide evidence showing that YM155 could act as a small molecule survivin inhibitor on survivin-rich expressed SCC9 cells in culture as well as when grown as tumor in a xenograft model. We also suggest that survivin could be further developed as a potential therapeutic agent for the treatment of survivin-rich expressed OSCC.

Jafarlou M, Baradaran B, Shanehbandi D, et al.
siRNA-mediated inhibition of survivin gene enhances the anti-cancer effect of etoposide in U-937 acute myeloid leukemia cells.
Cell Mol Biol (Noisy-le-grand). 2016; 62(6):44-9 [PubMed] Related Publications
Acute myeloid leukemia (AML) is one of the most frequent types of leukemia which mostly affects adult people. Resistance to therapeutic drugs is considered as a major clinical concern resulting in a weaker response to chemotherapy, disease relapse and decreased survival rate. Survivin, a member of Inhibitor of Apoptosis Proteins (IAPs), is associated with drug resistance and inhibition of apoptotic mechanisms in numerous hematological malignancies. In the present study, we examined the combined effect of etoposide and siRNA-mediated silencing of survivin on U-937 acute myeloid leukemia cells. The AML cells were transfected with survivin specific siRNA and gene knockdown was confirmed by quantitative real time PCR and western blotting. Subsequently, U-937 cells were assessed for response to etoposide treatment and apoptosis rate was measured with flowcytometery. The cytotoxic effects in siRNA-etoposide group were measured and compared to etoposide single therapy group. Survivin siRNA effectively knocked down the mRNA and protein levels of survivin, which led to lower cell proliferation and enhanced apoptosis. Furthermore, combined treatment of etoposide and survivin siRNA synergistically increased the cell toxic effects of etoposide and its ability to induce apoptosis.

He XJ, Zhang Q, Ma LP, et al.
Aberrant Alternative Polyadenylation is Responsible for Survivin Up-regulation in Ovarian Cancer.
Chin Med J (Engl). 2016; 129(10):1140-6 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Survivin is an oncoprotein silenced in normal mature tissues but reactivated in serous ovarian cancer (SOC). Although transcriptional activation is assumed for its overexpression, the long 3'-untranslated region (3'-UTR) in survivin gene, which contains many alternate polyadenylation (APA) sites, implies a propensity for posttranscriptional control and therefore was the aim of our study.
METHODS: The abundance of the coding region, the proximal and the distal region of survivin mRNA 3'-UTR, was evaluated by real-time polymerase chain reaction (PCR) in SOC samples, cell lines, and normal fallopian tube (NFT) tissues. The APA sites were confirmed by rapid amplification of cDNA 3' ends and DNA sequencing. Real-time PCR were used to screen survivin-targeting microRNAs (miRNAs) that were inversely correlated with survivin. The expression of an inversely correlated miRNA was restored by pre-miRNA transfection or induction with a genotoxic agent to test its inhibitory effect on survivin overexpression.
RESULTS: Varying degrees of APA were observed in SOC by comparing the abundance of the proximal and the distal region of survivin 3'-UTR, and changes of 3'-UTR correlated significantly with survivin expression (r = 0.708, P< 0.01). The main APA sites are proved at 1197 and 1673 of survivin 3'-UTR by DNA sequencing. Higher level of 3'-UTR proximal region than coding region was observed in NFT, as well as in SOC and cell lines. Among the survivin-targeting miRNAs, only a few highly expressed miRNAs were inversely correlated with survivin levels, and they mainly targeted the distal part of the 3'-UTR. However, in ovarian cancer cells, restoration of an inversely correlated miRNA (miR-34c) showed little effect on survivin expression.
CONCLUSIONS: In NFT tissues, survivin is not transcriptionally silenced but regulate posttranscriptionally. In SOC, aberrant APA leads to the shortening of survivin 3'-UTR which enables it to escape the negative regulation of miRNAs and is responsible for survivin up-regulation.

Yang AQ, Wang PJ, Huang T, et al.
Effects of monomethoxypolyethylene glycol-chitosan nanoparticle-mediated dual silencing of livin and survivin genes in prostate cancer PC-3M cells.
Genet Mol Res. 2016; 15(2) [PubMed] Related Publications
Monomethoxypolyethylene glycol-chitosan (mPEG-CS) nanoparticles were used as interfering RNA carriers to transfect human prostate cancer PC-3M cells to evaluate the effects of livin and survivin gene silencing on the proliferation and apoptosis. mPEG-CS nanoparticles with sizes of approximately 60 nm were first synthesized by ionic crosslinking. Through electrostatic adsorption, mPEG-CS-livin short hairpin RNA (shRNA), mPEG-CS-survivin shRNA, and mPEG-CS-(livin shRNA + survivin shRNA) nanoparticles were then prepared to transfect PC-3M cells. The mRNA and protein expression levels of livin and survivin were measured by reverse transcription-PCR and western blotting, respectively. The inhibitory effects of down-regulated livin and survivin gene expression on the cell proliferation were evaluated by MTT assay. Cell apoptosis was assessed visually using Hoechst staining. Livin and survivin expression levels in all shRNA interference groups were effectively down-regulated at both the mRNA and protein levels. Dual silencing of livin and survivin genes markedly inhibited cell proliferation and facilitated apoptosis, with better outcomes than those of individual shRNA treatments. mPEG-CS nanoparticle-mediated dual shRNA interference of livin and survivin genes significantly reduced the expression levels in PC-3M cells, inhibited proliferation, and promoted apoptosis. As these effects were superior to single interference, this method may have synergistic effects.

Jiao D, Zhang XD
Myricetin suppresses p21-activated kinase 1 in human breast cancer MCF-7 cells through downstream signaling of the β-catenin pathway.
Oncol Rep. 2016; 36(1):342-8 [PubMed] Related Publications
As a main active compound in the bark of waxberry (Myrica rubra), myricetin is a macrocyclic diarylheptanoid, and can trigger the apoptosis of HeLa and PC3 cells. The aim of the present study was to elucidate the anticancer effect of myricetin on human breast cancer MCF-7 cells and to explore the possible mechanisms of action. MCF-7 cells were treated with different concentrations of myricetin (0-80 µM) for 12, 24 and 48 h. In the present study, we found that myricetin suppressed the cell viability of the MCF-7 cells at least partly through the induction of apoptosis as determined by MTT assay and flow cytometry. Western blot analysis revealed that myricetin effectively suppressed the protein expression of p21-activated kinase 1 (PAK1), MEK and phosphorylated extracellular mitogen-activated protein kinase (ERK1/2). In addition, treatment of myricetin activated glycogen synthase kinase-3β (GSK3β) and Bax protein expression, and inhibited β-catenin/cyclin D1/proliferating cell nuclear antigen (PCNA)/survivin and promoted caspase-3 activity in the MCF-7 cells. These results demonstrated that myricetin suppressed the cell viability of human breast cancer MCF-7 cells through PAK1/MEK/ERK/GSK3β/β-catenin/cyclin D1/PCNA/survivin/Bax-caspase-3 signaling.

Lim SL, Mustapha NM, Goh YM, et al.
Metastasized lung cancer suppression by Morinda citrifolia (Noni) leaf compared to Erlotinib via anti-inflammatory, endogenous antioxidant responses and apoptotic gene activation.
Mol Cell Biochem. 2016; 416(1-2):85-97 [PubMed] Related Publications
Metastasized lung and liver cancers cause over 2 million deaths annually, and are amongst the top killer cancers worldwide. Morinda citrifolia (Noni) leaves are traditionally consumed as vegetables in the tropics. The macro and micro effects of M. citrifolia (Noni) leaves on metastasized lung cancer development in vitro and in vivo were compared with the FDA-approved anti-cancer drug Erlotinib. The extract inhibited the proliferation and induced apoptosis in A549 cells (IC50 = 23.47 μg/mL) and mouse Lewis (LL2) lung carcinoma cells (IC50 = 5.50 μg/mL) in vitro, arrested cancer cell cycle at G0/G1 phases and significantly increased caspase-3/-8 without changing caspase-9 levels. The extract showed no toxicity on normal MRC5 lung cells. Non-small-cell lung cancer (NSCLC) A549-induced BALB/c mice were fed with 150 and 300 mg/kg M. citrifolia leaf extract and compared with Erlotinib (50 mg/kg body weight) for 21 days. It significantly increased the pro-apoptotic TRP53 genes, downregulated the pro-tumourigenesis genes (BIRC5, JAK2/STAT3/STAT5A) in the mice tumours, significantly increased the anti-inflammatory IL4, IL10 and NR3C1 expression in the metastasized lung and hepatic cancer tissues and enhanced the NFE2L2-dependent antioxidant responses against oxidative injuries. The extract elevated serum neutrophils and reduced the red blood cells, haemoglobin, corpuscular volume and cell haemoglobin concentration in the lung cancer-induced mammal. It suppressed inflammation and oedema, and upregulated the endogenous antioxidant responses and apoptotic genes to suppress the cancer. The 300 mg/kg extract was more effective than the 50 mg/kg Erlotinib for most of the parameters measured.

Cruz RQ, Morais CM, Cardoso AM, et al.
Enhancing glioblastoma cell sensitivity to chemotherapeutics: A strategy involving survivin gene silencing mediated by gemini surfactant-based complexes.
Eur J Pharm Biopharm. 2016; 104:7-18 [PubMed] Related Publications
Glioblastoma (GBM), the highest grade astrocytoma, is one of the most aggressive and challenging cancers to treat. The standard treatment is usually limited due to the intrinsic resistance of GBM to chemotherapy and drug non-specific effects. Therefore, new therapeutic strategies need to be developed to target tumor cells, sparing healthy tissues. In this context, the inhibitor-of-apoptosis protein (IAP) survivin emerges as an ideal target for a gene silencing approach, since it is sharply differentially expressed in cancer tissues. In this work, two different families of cationic gemini surfactants (bis-quat conventional and serine-derived) were tested regarding their efficiency to deliver small interfering RNAs (siRNAs) in a human GBM cell line (U87), in order to select an effective siRNA anti-survivin carrier. Importantly, survivin downregulation combined with administration of the chemotherapeutic agents temozolomide or etoposide resulted in a synergistic cytotoxic effect, thus revealing to be a promising strategy to reduce the chemotherapeutic doses for GBM treatment.

Liu ZF, Liang ZQ, Li L, et al.
MiR-335 functions as a tumor suppressor and regulates survivin expression in osteosarcoma.
Eur Rev Med Pharmacol Sci. 2016; 20(7):1251-7 [PubMed] Related Publications
OBJECTIVE: Previous studies have shown that miR-335 plays an anti-tumor role in several types of cancer. However, whether it is able to regulate the tumorigenesis of osteosarcoma (OS) has not been fully investigated. The present study was designed to study its potential role in regulating apoptosis of OS cells.
MATERIALS AND METHODS: The expression of miR-335 in a total of 18 paired OS tumor tissues and adjacent non-cancerous tissues was measured by Real-time PCR, and its different expression in OS cell lines was also measured. The effect of miR-335 on apoptosis was measured by MTT assay, caspase-3 activity assay and TUNEL assay. The effect of survivin inhibition on apoptosis of OS cells was determined by MTT assay and western blot. Luciferase reporter assay and western blot were conducted to confirm the relationship between miR-335 and the 3'UTR of survivin mRNA.
RESULTS: MiR-335 expression was found to be significantly downregulated in OS tumor tissues and OS cell lines. Overexpression of miR-335 led to decreased cell viability and increased apoptosis. MiR-335 directly targeted the 3'UTR of survivin mRNA and suppressed survivin gene expression, and inhibition of survivin exhibited similar effects to miR-335 overexpression.
CONCLUSIONS: MiR-335 might function as a tumor suppressor in OS, and downregulation of miR-335 in OS cells contributes to the decreased apoptotic potential of OS cells through derepression of survivin.

Duan L, Hu X, Jin Y, et al.
Survivin protein expression is involved in the progression of non-small cell lung cancer in Asians: a meta-analysis.
BMC Cancer. 2016; 16:276 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Surviving expression might serve as a prognostic biomarker predicting the clinical outcome of non-small cell lung cancer (NSCLC). The study was conducted to explore the potential correlation of survivin protein expression with NSCLC and its clinicopathologic characteristics.
METHODS: PubMed, Medline, Cochrane Library, CNKI and Wanfang database were searched through January 2016 with a set of inclusion and exclusion criteria. Data was extracted from these articles and all statistical analysis was conducted by using Stata 12.0.
RESULTS: A total of 28 literatures (14 studies in Chinese and 14 studies in English) were enrolled in this meta-analysis, including 3206 NSCLC patients and 816 normal controls. The result of meta-analysis demonstrated a significant difference of survivin positive expression between NSCLC patients and normal controls (RR = 7.16, 95 % CI = 4.63-11.07, P < 0.001). To investigate the relationship of survivin expression and clinicopathologic characteristics, we performed a meta-analysis in NSCLC patients. Our results indicates survivin expression was associated with histological differentiation, tumor-node-metastasis (TNM) stage and lymph node metastasis (LNM) (RR = 0.80, 95 % CI = 0.73-0.87, P < 0.001; RR = 0.75, 95 % CI = 0.67-0.84, P < 0.001; RR = 1.14, 95 % CI = 1.01-1.29, P = 0.035, respectively), but not pathological type and tumor size. (RR = 1.00, 95 % CI = 0.93-1.07, P = 0.983; RR = 0.95, 95 % CI = 0.86-1.05, P = 0.336, respectively).
CONCLUSION: Higher expression of survivin in NSCLC patients was found when compared to normal controls. Survivin expression was associated with the clinicopathologic characteristics of NSCLC and may serves as an important biomarker for NSCLC progression.

Sam S, Sam MR, Esmaeillou M, Safaralizadeh R
Effective Targeting Survivin, Caspase-3 and MicroRNA-16-1 Expression by Methyl-3-pentyl-6-methoxyprodigiosene Triggers Apoptosis in Colorectal Cancer Stem-Like Cells.
Pathol Oncol Res. 2016; 22(4):715-23 [PubMed] Related Publications
Over-expression of the proto-oncogene survivin in colorectal cancer stem cells (CCSCs) is thought to be one the primary causes for therapy failure. It has also been reported that tumor suppressor miR-16-1 is down-regulated in colorectal cancer (CRC) cells. Therefore, the search for new anti-proliferative agents which target survivin or miR-16-1 in CCSCs is warranted. Several studies have shown that prodigiosin isolated from cell wall of Serratia marcescens induces apoptosis in different kinds of cancer cells. Here, we investigated the effects of prodigiosin on HCT-116 cells that serve as a model for CRC initiating cells with stem-like cells properties. HCT-116 cells were treated with 100, 200 and 400 nM prodigiosin after which cell number, viability, growth-rate, survivin and miRNA-16-1 expression, caspase-3 activation and apoptotic rate were evaluated. Prodigiosin decreased significantly growth-rate in a dose-and time-dependent manner. After a 48 h treatment with 100, 200 and 400 nM prodigiosin, growth-rates were measured to be 84.4 ± 9.2 %, 58 ± 6.5 % and 46.3 ± 5.2 %, respectively, compared to untreated cells. We also found that treatment for 48 h with indicated concentrations of prodigiosin resulted in 41 %, 54.5 % and 63 % decrease in survivin mRNA levels and induced 32 %, 48 % and 61 % decrease in survivin protein levels as well as resulted in 128.3 ± 10 %, 178.7 ± 6.1 % and 205 ± 7.6 % increase in caspase-3 activation respectively compared to untreated cells. Prodigiosin caused a significant increase in miRNA-16-1 expression at a concentration of 100 nM and treatment with different concentrations of prodigiosin resulted in 2.2- to 3-fold increase in miRNA-16-1/survivin ratios compared to untreated cells. An increase in number of apoptotic cells ranging from 28.2 % to 86.8 % was also observed with increasing prodigiosin concentrations. Our results provide the first evidence that survivin and miRNA-16-1 as potential biomarkers could be targeted in CRC initiating cells with stem-like cells properties by prodigiosin and this compound with high pro-apoptotic capacity represents the possibility of its therapeutic application directed against CCSCs.

Domińska K, Ochędalski T, Kowalska K, et al.
Interaction between angiotensin II and relaxin 2 in the progress of growth and spread of prostate cancer cells.
Int J Oncol. 2016; 48(6):2619-28 [PubMed] Related Publications
Deregulation of locally secreted hormones, such as angiotensin II (Ang II) and relaxin 2 (RLN2), has been linked to a higher risk of select cancers or a poor prognosis in patients. In this study, for the first time a common effect of Ang II and RLN2 in relation to various aspects of prostate cancer development and metastasis are presented. Four independent colorimetric assays were used to analyze cell viability and proliferation. The changes of cell adhesion to extracellular matrix proteins and invasion/aggressiveness ability of prostate cancer cells (LNCaP, PC3) before and after peptides treatment, were also investigated. The findings suggest that the both investigated systems, have an impact on cell growth/division or spread, to some degree via overlapping signal transduction pathways. Intermediate or sometimes poorer results were achieved by using a combination of both hormones than when each was used individually. It seems that Ang II and RLN2 can play a significant role in increasing the aggressiveness of prostate tumors by up-regulating BIRC5 expression and MMP-2 and MMP-9 secretion. In addition, we speculate that Ang II and RLN2 are involved in the transition from the androgen-dependent to the androgen-independent phenotype via modulation of the expression of androgen receptors.

Gulluoglu S, Tuysuz EC, Kuskucu A, et al.
The potential function of microRNA in chordomas.
Gene. 2016; 585(1):76-83 [PubMed] Related Publications
Little is known about the molecular biology of chordomas, which are rare, chemoresistant tumors with no well-established treatment. miRNAs regulate gene networks and pathways. We aimed to evaluate the effects of dysregulated miRNA in chordomas would help reveal the underlying mechanisms of chordoma initiation and progression. In this study, miR-31, anti-miR-140-3p, anti-miR148a, and miR-222 were transiently transfected to chordoma cell lines and an MTS assay, apoptosis assay, and cell-cycle analysis were conducted to evaluate the effects. The mRNA level of predicted and confirmed targets of each miRNA, as well as the EMT and MET markers of U-CH1 and MUG-Chor1, were assessed with real-time polymerase chain reaction. Transient transfection of miRNA mimics was achieved, as each mimic increased or decreased the level of its corresponding miRNA. miR-31 decreased cell viability in MUG-Chor1 and U-CH2 after 72h, which is consistent with previous findings for U-CH1. Both miR-31 and anti-miR-148a induced apoptosis in all three cell lines. Although each miRNA had a similar pattern, miR-31 had the most effective S-phase arrest in all three cell lines. RDX, MET, DNMT1, DNMT3B, TRPS1, BIRC5, and KIT were found to be targeted by the selected miRNAs. The level of miR-222 in chordoma cell lines U-CH1 and MUG-Chor1 correlated positively with EMT markers and negatively with MET markers. This study uncovered the potential of miR-31, miR-140-3p, miR-148a, and miR-222-3p to be key molecules in the cell viability, cell cycle, and apoptosis in chordomas, as well as initiation, differentiation, and progression.

Ueno T, Uehara S, Nakahata K, Okuyama H
Survivin selective inhibitor YM155 promotes cisplatin‑induced apoptosis in embryonal rhabdomyosarcoma.
Int J Oncol. 2016; 48(5):1847-54 [PubMed] Related Publications
Survivin, a member of the inhibitor of apoptosis protein family, functions as a key regulator of programmed cell death. YM155 is a small molecule that selectively inhibits survivin. We investigated the effect of YM155 on survivin suppression in the human rhabdomyosarcoma (RMS) cell line RD. The efficacy of YM155 in combination with cisplatin was also determined in a xenograft model. The effect of YM155 on survivin expression in the RD cell line was examined at both mRNA and protein levels using real-time PCR and western blot analysis. RD cells were cultured with various concentrations of YM155, then cisplatin was added to the medium and the anti-proliferation response was determined. Cell growth was evaluated by WST-8 assay. Finally, the efficacy of YM155 combined with cisplatin was examined in an established xenograft model. Survivin mRNA levels in the RD cell line were decreased to 72 and 24% at 24 and 48 h, respectively, after 10 nM of YM155 was added. YM155 also decreased the levels of survivin protein. YM155 treatment (10 nM) inhibited cell proliferation of RD in a dose-dependent manner in vitro, with 58% of cells viable at 48 h. When cultured with 10 nM of YM155 and 10 µM cisplatin, RD cells demonstrated only 25% of the growth observed when cultured with cisplatin alone. YM155 in combination with cisplatin significantly inhibited tumor growth by 13% compared with control (P<0.0001) in RD xenograft tumors. YM155 increased the sensitivity of cisplatin by suppressing survivin in the embryonal RMS cell line RD. Further studies should investigate the use of YM155 as an apoptosis inducer, either alone or in combination with cisplatin, for the treatment of malignant RMS.

Hu W, Jin P, Liu W
Periostin Contributes to Cisplatin Resistance in Human Non-Small Cell Lung Cancer A549 Cells via Activation of Stat3 and Akt and Upregulation of Survivin.
Cell Physiol Biochem. 2016; 38(3):1199-208 [PubMed] Related Publications
BACKGROUND/AIMS: Periostin is upregulated in non-small cell lung cancer (NSCLC). This study was done to explore the function of periostin in the development of cisplatin (CDDP) resistance in NSCLC.
METHODS: The effects of overexpression or knockdown of periostin on CDDP sensitivity was examined in A549 cells. The involvement of signal transducer and activator of transcription 3 (Stat3) and Akt signaling in the action of periostin was checked. The in vivo effect of periostin silencing on CDDP susceptibility was determined in a mouse xenograft model.
RESULTS: Periostin was significantly upregulated in CDDP-resistant A549 cells, compared to parental controls. Overexpression of periostin rendered A549 cells more resistant to CDDP-induced apoptosis and enhanced Stat3 and Akt phosphorylation and survivin expression. Periostin-mediated protection against CDDP-induced apoptosis was compromised by downregulation of survivin. Furthermore, knockdown of periostin re-sensitized CDDP-resistant A549 cells to CDDP. After CDDP treatment, greater volume reduction was observed in periostin-silenced xenograft tumors than in control tumors, which was accompanied by reduced levels of phosphorylated Stat3 and survivin in periostin-depleted tumors.
CONCLUSION: In conclusion, periostin promotes CDDP resistance in NSCLC cells largely through activation of Stat3 and Akt and upregulation of survivin and thus represents a promising target for overcoming CDDP resistance.

Fragni M, Bonini SA, Stabile A, et al.
Inhibition of Survivin Is Associated with Zoledronic Acid-induced Apoptosis of Prostate Cancer Cells.
Anticancer Res. 2016; 36(3):913-20 [PubMed] Related Publications
BACKGROUND/AIM: Evidence suggests that zoledronic acid (ZA) exerts direct antitumor effects on cancer cells but the underlying mechanisms of these actions are unknown. This study investigated the possible involvement of survivin in the antiproliferative effects of ZA in prostate cancer.
MATERIALS AND METHODS: 3-(4,5-dimethyl-2-thiazol)-2,5-diphenyl-2H-tetrazolium bromide (MTT) dye reduction assay was used to assess cell viability and acridine orange/ethidium bromide double staining to analyze cell death. Human Apoptosis Array evaluated the expression of apoptosis-related proteins. Survivin protein was measured by western blot technique and miR-203 levels were quantified by quantitative real-time polymerase chain reaction.
RESULTS: ZA induced inhibition of cell proliferation and apoptosis activation, with down-regulation of survivin protein. A negative regulation at gene expression level may be hypothesized because we observed a significant decrease of survivin mRNA level and an increase of miR-203 expression after ZA exposure.
CONCLUSION: This study provides evidence that ZA may directly inhibit cancer cell proliferation, identifying survivin as one of its downstream targets.

Qi G, Kudo Y, Tang B, et al.
PARP6 acts as a tumor suppressor via downregulating Survivin expression in colorectal cancer.
Oncotarget. 2016; 7(14):18812-24 [PubMed] Free Access to Full Article Related Publications
Poly (ADP-ribose) polymerases (PARPs) are enzymes that transfer ADP-ribose groups to target proteins and are involved in a variety of biological processes. PARP6 is a novel member, and our previous findings suggest that PARP6 may act as a tumor suppressor via suppressing cell cycle progression. However, it is still unclear that PARP6 function besides growth suppression in colorectal cancer (CRC). In this study, we examined tumor suppressive roles of PAPR6 in CRC cells both in vitro and in vivo. We found that PARP6 inhibited colony formation, invasion and migration as well as cell proliferation. Moreover, ectopic overexpression of PARP6 decreased Survivin expression, which acts as an oncogene and is involved in apoptosis and mitosis. We confirmed the inverse correlation between PARP6 and Survivin expression in CRC cases by immunohistochemistry. Importantly, CRC cases with downregulation of PARP6 and upregulation of Survivin showed poor prognosis. In summary, PARP6 acts as a tumor suppressor via downregulating Survivin expression in CRC. PARP6 can be a novel diagnostic and therapeutic target together with Survivin for CRC.

Niwa AM, D Epiro GF, Marques LA, et al.
Salinomycin efficiency assessment in non-tumor (HB4a) and tumor (MCF-7) human breast cells.
Naunyn Schmiedebergs Arch Pharmacol. 2016; 389(6):557-71 [PubMed] Related Publications
The search for anticancer drugs has led researchers to study salinomycin, an ionophore antibiotic that selectively destroys cancer stem cells. In this study, salinomycin was assessed in two human cell lines, a breast adenocarcinoma (MCF-7) and a non-tumor breast cell line (HB4a), to verify its selective action against tumor cells. Real-time assessment of cell proliferation showed that HB4a cells are more resistant to salinomycin than MCF-7 tumor cell line, and these data were confirmed in a cytotoxicity assay. The half maximal inhibitory concentration (IC50) values show the increased sensitivity of MCF-7 cells to salinomycin. In the comet assay, only MCF-7 cells showed the induction of DNA damage. Flow cytometric analysis showed that cell death by apoptosis/necrosis was only induced in the MCF-7 cells. The increased expression of GADD45A and CDKN1A genes was observed in all cell lines. Decreased expression of CCNA2 and CCNB1 genes occurred only in tumor cells, suggesting G2/M cell cycle arrest. Consequently, cell death was activated in tumor cells through strong inhibition of the antiapoptotic genes BCL-2, BCL-XL, and BIRC5 genes in MCF-7 cells. These data demonstrate the selectivity of salinomycin in killing human mammary tumor cells. The cell death observed only in MCF-7 tumor cells was confirmed by gene expression analysis, where there was downregulation of antiapoptotic genes. These data contribute to clarifying the mechanism of action of salinomycin as a promising antitumor drug and, for the first time, we observed the higher resistance of HB4a non-tumor breast cells to salinomycin.

Wu J, Zhao S, Zhang J, et al.
Over-expression of survivin is a factor responsible for differential responses of ovarian cancer cells to S-allylmercaptocysteine (SAMC).
Exp Mol Pathol. 2016; 100(2):294-302 [PubMed] Related Publications
While investigating the inhibitory effect of S-allylmercaptocysteine (SAMC), a garlic derivative, on ovarian cancer, we subjected three ovarian cancer cell lines, HO8910, HO8910PM, and SKOV3, to SAMC treatment. In vivo and in vitro experiments showed that only HO8910 and SKOV3 cells were highly sensitive to SAMC, whereas HO8910PM cells were resistant to SAMC. Subsequently, we examined the apoptosis-related genes in the three cell lines. We found that survivin gene was highly expressed in HO8910PM cells. Down regulation of survivin gene in HO8910PM cells with small interference RNA (siRNA), resulted in increased sensitivity to SAMC together with a decrease in invasiveness of tumor cells. We therefore concluded that the S-allylmercaptocysteine suppresses both the proliferation and distant metastasis of epithelial ovarian cancer cells, insensitivity of HO8910PM cells to SAMC was closely related to the high level of survivin expression and that combination of SAMC treatment together with survivin knockdown might be a potential strategy for treatment of certain variants of ovarian cancers.

Tiptiri-Kourpeti A, Spyridopoulou K, Santarmaki V, et al.
Lactobacillus casei Exerts Anti-Proliferative Effects Accompanied by Apoptotic Cell Death and Up-Regulation of TRAIL in Colon Carcinoma Cells.
PLoS One. 2016; 11(2):e0147960 [PubMed] Free Access to Full Article Related Publications
Probiotic microorganisms such as lactic acid bacteria (LAB) exert a number of strain-specific health-promoting activities attributed to their immunomodulatory, anti-inflammatory and anti-carcinogenic properties. Despite recent attention, our understanding of the biological processes involved in the beneficial effects of LAB strains is still limited. To this end, the present study investigated the growth-inhibitory effects of Lactobacillus casei ATCC 393 against experimental colon cancer. Administration of live Lactobacillus casei (as well as bacterial components thereof) on murine (CT26) and human (HT29) colon carcinoma cell lines raised a significant concentration- and time-dependent anti-proliferative effect, determined by cell viability assays. Specifically, a dramatic decrease in viability of colon cancer cells co-incubated with 10(9) CFU/mL L. casei for 24 hours was detected (78% for HT29 and 52% for CT26 cells). In addition, live L. casei induced apoptotic cell death in both cell lines as revealed by annexin V and propidium iodide staining. The significance of the in vitro anti-proliferative effects was further confirmed in an experimental tumor model. Oral daily administration of 10(9) CFU live L. casei for 13 days significantly inhibited in vivo growth of colon carcinoma cells, resulting in approximately 80% reduction in tumor volume of treated mice. Tumor growth inhibition was accompanied by L. casei-driven up-regulation of the TNF-related apoptosis-inducing ligand TRAIL and down-regulation of Survivin. Taken together, these findings provide evidence for beneficial tumor-inhibitory, anti-proliferative and pro-apoptotic effects driven by this probiotic LAB strain.

Zhang Y, Zhou SY, Yan HZ, et al.
miR-203 inhibits proliferation and self-renewal of leukemia stem cells by targeting survivin and Bmi-1.
Sci Rep. 2016; 6:19995 [PubMed] Free Access to Full Article Related Publications
Drug resistance is one of the leading causes of failed cancer therapy in the treatment of acute myeloid leukemia. Although the mechanisms of resistance are poorly understood, they may be related to the presence of leukemia stem cells (LSCs). Down-regulation of the miR-203 reportedly contributes to oncogenesis and chemo-resistance in multiple cancers. We found that miR-203 expression was down-regulated in CD34 + AML cells as compared with CD34- cells isolated from patients as well as in LSC-enriched (CD34 + CD38-) cell lines KG-1a or MOLM13. Additionally, re-expression of miR-203 led to decreased cell proliferation, self-renewal, and sphere formation in LSCs. Moreover, miR-203 was found to directly target the 3'un-translated regions of survivin and Bmi-1 mRNAs affecting proliferation and self-renewal in LSCs. In this study, we identified a novel miR-203/survivin/Bmi-1 axis involved in the regulation of biological properties of LSCs. This axis may represent a new therapeutic target for acute myeloid leukemia and a potential prognosis/diagnostic marker for LSCs therapy.

Further References

Suzuki A, Ito T, Kawano H, et al.
Survivin initiates procaspase 3/p21 complex formation as a result of interaction with Cdk4 to resist Fas-mediated cell death.
Oncogene. 2000; 19(10):1346-53 [PubMed] Related Publications
Caspase 3 is an essential death factor for the Fas-mediated cell death, and its inactivation in cells is initiated by an interaction with p21 on mitochondria or with IAP family member ILP. Survivin is also a member of IAP family and is specifically expressed during embryogenesis and in tumor cells and suppresses cell death signaling. In our current study, we demonstrated that Survivin translocation into the nucleus is dependent on Fas stimulation and cell proliferation. Survivin also interacts with the cell cycle regulator Cdk4, leading to Cdk2/Cyclin E activation and Rb phosphorylation. As a result of Survivin/Cdk4 complex formation, p21 is released from its complex with Cdk4 and interacts with mitochondrial procaspase 3 to suppress Fas-mediated cell death. Here, we propose that Survivin supports procaspase 3/p21 complex formation as a result of interaction with Cdk4 resulting in suppression of cell death signaling.

Mahotka C, Wenzel M, Springer E, et al.
Survivin-deltaEx3 and survivin-2B: two novel splice variants of the apoptosis inhibitor survivin with different antiapoptotic properties.
Cancer Res. 1999; 59(24):6097-102 [PubMed] Related Publications
Recently, a novel antiapoptosis gene, i.e., survivin, was identified as a structurally unique member of the inhibitor of apoptosis protein family. Survivin expression is turned off during fetal development and not found in non-neoplastic adult human tissues but is again turned on in the most common human cancers. The antiapoptotic properties of survivin might provide a significant growth advantage in tumors and possibly also contribute to chemoresistance of cancer. Therefore, we analyzed the expression of survivin in human renal cell carcinomas (RCCs), known to be largely resistant to chemotherapy. Northern blot analysis and RT-PCR revealed survivin expression in newly established RCC cell lines (n = 11) of all major histological types. Moreover, we identified two novel splice variants of survivin, lacking exon 3 (survivin-deltaEx3) or retaining a part of intron 2 as a cryptic exon (survivin-2B). Both sequence alterations cause marked changes in the structure of the corresponding proteins, including structural modifications of the baculovirus inhibitor of apoptosis protein repeat domain. The role of the novel isoforms in the regulation of apoptosis was assessed in transfection experiments, showing conservation of antiapoptotic properties for survivin-deltaEx3 and a markedly reduced antiapoptotic potential for survivin-2B. In conclusion, our observations suggest a complex regulatory balance between the different isoforms of survivin, which might determine the response to proapoptotic stimuli, not only in human RCCs but also in fetal tissues and other types of cancer.

Li F, Ambrosini G, Chu EY, et al.
Control of apoptosis and mitotic spindle checkpoint by survivin.
Nature. 1998; 396(6711):580-4 [PubMed] Related Publications
Progression of the cell cycle and control of apoptosis (programmed cell death) are thought to be intimately linked processes, acting to preserve homeostasis and developmental morphogenesis. Although proteins that regulate apoptosis have been implicated in restraining cell-cycle entry and controlling ploidy (chromosome number), the effector molecules at the interface between cell proliferation and cell survival have remained elusive. Here we show that a new inhibitor of apoptosis (IAP) protein, survivin, is expressed in the G2/M phase of the cell cycle in a cycle-regulated manner. At the beginning of mitosis, survivin associates with microtubules of the mitotic spindle in a specific and saturable reaction that is regulated by microtubule dynamics. Disruption of survivin-microtubule interactions results in loss of survivin's anti-apoptosis function and increased caspase-3 activity, a mechanism involved in cell death, during mitosis. These results indicate that survivin may counteract a default induction of apoptosis in G2/M phase. The overexpression of survivin in cancer may overcome this apoptotic checkpoint and favour aberrant progression of transformed cells through mitosis.

Ambrosini G, Adida C, Altieri DC
A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma.
Nat Med. 1997; 3(8):917-21 [PubMed] Related Publications
Inhibitors of programmed cell death (apoptosis) aberrantly prolonging cell viability may contribute to cancer by facilitating the insurgence of mutations and by promoting resistance to therapy. Despite the identification of several new apoptosis inhibitors related to bcl-2 or to the baculovirus IAP gene, it is not clear whether apoptosis inhibition plays a general role in neoplasia. Here, we describe a new human gene encoding a structurally unique IAP apoptosis inhibitor, designated survivin. Survivin contains a single baculovirus IAP repeat and lacks a carboxyl-terminal RING finger. Present during fetal development, survivin is undetectable in terminally differentiated adult tissues. However, survivin becomes prominently expressed in transformed cell lines and in all the most common human cancers of lung, colon, pancreas, prostate and breast, in vivo. Survivin is also found in approximately 50% of high-grade non-Hodgkin's lymphomas (centroblastic, immunoblastic), but not in low-grade lymphomas (lymphocytic). Recombinant expression of survivin counteracts apoptosis of B lymphocyte precursors deprived of interleukin 3 (IL-3). These findings suggest that apoptosis inhibition may be a general feature of neoplasia and identify survivin as a potential new target for apoptosis-based therapy in cancer and lymphoma.

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