Gene Summary

Gene:CASP2; caspase 2
Aliases: ICH1, NEDD2, CASP-2, NEDD-2, PPP1R57
Summary:This gene encodes a member of the cysteine-aspartic acid protease (caspase) family. Caspases mediate cellular apoptosis through the proteolytic cleavage of specific protein substrates. The encoded protein may function in stress-induced cell death pathways, cell cycle maintenance, and the suppression of tumorigenesis. Increased expression of this gene may play a role in neurodegenerative disorders including Alzheimer's disease, Huntington's disease and temporal lobe epilepsy. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2011]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 15 March, 2017


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 15 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 15 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

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

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

Latest Publications: CASP2 (cancer-related)

Liu J, Dou Y, Sheng M
Inhibition of microRNA-383 has tumor suppressive effect in human epithelial ovarian cancer through the action on caspase-2 gene.
Biomed Pharmacother. 2016; 83:1286-1294 [PubMed] Related Publications
BACKGROUND: MicroRNAs are important cancer regulators. In this work, we examined the expression pattern and mechanistic implications of microRNA-383 (miR-383) in human epithelial ovarian cancer (EOC).
METHODS: Gene expression level of miR-383 was compared by qRT-PCR between EOC cell lines and normal ovarian epithelial cell line, and between clinical EOC tumors and adjacent non-tumor ovarian epithelial tissues. Endogenous miR-383 was downregulated through lentiviral infection. Its effects on regulating EOC proliferation, cell cycle, invasion and in vivo explant development were assessed. Possible downstream target of miR-383 in EOC, human caspase-2 gene (CASP2), was evaluated by luciferase assay and qRT-PCR. CASP2 was then genetically knocked down by siRNA to assess its functional relationship with miR-383 in regulating EOC development both in vitro and in vivo.
RESULTS: MiR-383 was overexpressed in both immortal EOC cell lines and human EOC tumors. In stably miR-383-downregulated EOC cell lines, cancer proliferation, cell cycle progression, invasion and in vivo explant development were significantly suppressed. CASP2 was confirmed to be downstream of miR-383 in EOC. SiRNA-mediated CASP2 downregulation had reverse relationship with miR-383 downregulation in regulating EOC development both in vitro and in vivo.
CONCLUSION: Inhibition of miR-383 has profound tumor suppressing effect on EOC development. And the functional regulation of miR-383 in EOC is very likely inversely associated with CASP2 gene.

Tang L, Shen H, Li X, et al.
MiR-125a-5p decreases after long non-coding RNA HOTAIR knockdown to promote cancer cell apoptosis by releasing caspase 2.
Cell Death Dis. 2016; 7:e2137 [PubMed] Free Access to Full Article Related Publications
HOTAIR (homeobox transcript antisense RNA), one of the prototypical long non-coding RNAs, has been verified overexpressed in multiple carcinomas and has emerged as a promising novel anticancer target. Its well-established role is acting as a predictor of poor prognosis and promoting cancer cell metastasis. Recently, another important mission of HOTAIR was uncovered that targeting HOTAIR caused cancer cell apoptosis. Nevertheless, so far there is no published data elaborating the mechanism. Here, we report that microRNA miR-125a-5p decreases and releases caspase 2 to promote cancer cell apoptosis after HOTAIR knockdown. We applied siRNAs targeting HOTAIR to various cancer cells, and observed apoptosis in all of these cell lines. RNA sequencing detected that miR-125a-5p was decreased after HOTAIR knockdown and miR-125a-5p mimics could rescue the apoptosis induced by HOTAIR deficiency. Luciferase assays identified caspase 2, an initiator caspase, to be a new target of miR-125a-5p. Elevated expression and subsequent cleavage of caspase 2 was observed after HOTAIR knockdown or inhibition of miR-125a-5p. RNAi of caspase 2 could attenuate the apoptosis induced by HOTAIR knockdown. In 80 clinical colon cancer tissues, HOTAIR and miR-125a-5p levels were higher than adjacent tissues, whereas caspase 2 was lower. MiR-125a-5p expression level was significantly correlated with colon tumor size, lymph node metastasis and clinical stage. These findings indicate that miR-125a-5p decreases after HOTAIR knockdown to promote cancer cell apoptosis by releasing caspase 2. Our work reveals a previously unidentified apoptotic mechanism, which might be exploitable in anticancer drug development.

Dodurga Y, Seçme M, Eroğlu C, et al.
Investigation of the effects of a sulfite molecule on human neuroblastoma cells via a novel oncogene URG4/URGCP.
Life Sci. 2015; 143:27-34 [PubMed] Related Publications
AIM: The aim of this study is to determine the anticancer effect of sulfite on SH-SY5Y neuroblastoma cells in vitro conditions and elucidate underlying molecular mechanism of sulfite and explore its therapeutic activity.
MAIN METHODS: In this study, cytotoxic effects of sulfite in SH-SY5Y cels were detected over time in a dose dependent manner with the IC50 doses ranging from 0.5 to 10 mM. Genotoxic effect of sulfite was shown by comet assay. IC50 doses in the SH-SY5Y cells were detected as 5 mM. Expression profiles of the target genes related to apoptosis and cell cycle control were determined by quantitative RT-PCR. Protein changes were determined by western blot analysis.
KEY FINDINGS: URG4/URGCP, CCND1, CCND2, CDK4, CDK6, E2F4 and BCL-2 gene expression levels were significantly reduced and RB1, TP53, BAX, BID, CASP2, CASP3, CASP9 and DIABLO gene expressions were significantly increased in dose group cells. The mechanism of this result may be related to sulfite dependent inhibition of cell cycle at the G1 phase by down-regulating URG4/URGCP or CCND1, CDK4, CDK6 gene expression and stimulating apoptosis via the intrinsic pathway. Sulfite suppressed invasion and colony formation in SH-SY5Y cell line using matrigel invasion chamber and colony formation assay, respectively.
SIGNIFICANCE: It is thought that sulfite demonstrates anticarcinogenesis activity by affecting cell cycle arrest, apoptosis s, invasion, and colony formation on SH-SY5Y cells. Sulfite may be an effective agent for treatment of neuroblastoma as a single agent or in combination with other agents.

Eroğlu C, Seçme M, Bağcı G, Dodurga Y
Assessment of the anticancer mechanism of ferulic acid via cell cycle and apoptotic pathways in human prostate cancer cell lines.
Tumour Biol. 2015; 36(12):9437-46 [PubMed] Related Publications
Studies on genetic changes underlying prostate cancer and the possible signaling pathways are getting increased day by day, and new treatment methods are being searched for. The aim of the present study is to investigate the effects of ferulic acid (FA), a phenolic compound, on cell cycle, apoptosis, invasion, and colony formation in the PC-3 and LNCaP prostate cancer cells. The effect of FA on cell viability was determined via a 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) method. Total RNA was isolated with Tri Reagent. Expression of 84 genes for both cell cycle and apoptosis separately was evaluated by reverse transcriptase PCR (RT-PCR). Protein expressions were evaluated by Western blot analysis. Furthermore, apoptotic effects of FA were observed with terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL) assay. Effects of FA on cell invasion and colony formation were determined using Matrigel chamber and colony assay, respectively. The half maximal inhibitory concentration (IC50) dose of FA was found to be 300 μM in PC-3 cells and 500 μM in LNCaP cells. According to RT-PCR results, it was observed that FA inhibited cell proliferation by increasing the gene expressions of ATR, ATM, CDKN1A, CDKN1B, E2F4, RB1, and TP53 and decreasing the gene expressions of CCND1, CCND2, CCND3, CDK2, CDK4, and CDK6 in PC-3 cells. On the other hand, it was seen that FA suppressed cell proliferation by increasing in the gene expressions of CASP1, CASP2, CASP8, CYCS, FAS, FASLG, and TRADD and decreasing in the gene expressions of BCL2 and XIAP in LNCaP cells. In this study, protein expression of CDK4 and BCL2 genes significantly decreased in these cells. It could induce apoptosis in PC-3 and LNCaP cells. Also, it was observed that FA suppressed the invasion in PC-3 and LNCaP cells. Moreover, it suppressed the colony formation. In conclusion, it has been observed that FA may lead to cell cycle arrest in PC-3 cells while it may cause apoptosis in LNCaP cells.

Coutinho-Camillo CM, Lourenço SV, de Araújo Lima L, et al.
Expression of apoptosis-regulating miRNAs and target mRNAs in oral squamous cell carcinoma.
Cancer Genet. 2015 Jul-Aug; 208(7-8):382-9 [PubMed] Related Publications
Aberrations in the apoptotic mechanisms that cause excessive or deficient programmed cell death have been linked to a wide array of pathological conditions. In this study, using real-time reverse transcriptase-PCR, we analyzed the expression of apoptosis-regulating miRNAs (miR-15a, miR-16, miR-17-5p, miR-20a, miR-21, miR-29a, and miR-34a) in 20 oral squamous cell carcinoma and 5 normal oral mucosa tissue samples. Bioinformatic algorithms were used to identify the target genes of these miRNAs (BCL2, CASP2, CASP7, CASP8, DIABLO). The expression transcript levels of the target genes were measured in 50 oral squamous cell carcinoma and 10 normal oral mucosa tissue samples. We observed downregulation of miR-15a, miR-29a, and miR-34a in 50, 75, and 70% of samples, respectively. miR-16, miR-17-5p, miR-20a, and miR-21 expression was normal in 80, 75, 90, and 60% of samples, respectively. BCL2 transcripts were downregulated in 60% of samples, and normal-like expression was observed for CASP2, CASP7, CASP8, and DIABLO transcripts in 66, 82, 68, and 60% of samples, respectively. BCL2 expression was negative to weak, and that of proteins CASP2, CASP7, CASP8, and DIABLO was moderate to strong. Our study provides evidence of alterations in the expression of apoptosis-regulating miRNAs and genes in the apoptotic pathway, demonstrating that regulation of apoptosis is a hallmark of oral squamous cell carcinoma pathogenesis.

Zhao Z, Ma X, Sung D, et al.
microRNA-449a functions as a tumor suppressor in neuroblastoma through inducing cell differentiation and cell cycle arrest.
RNA Biol. 2015; 12(5):538-54 [PubMed] Free Access to Full Article Related Publications
microRNA-449a (miR-449a) has been identified to function as a tumor suppressor in several types of cancers. However, the role of miR-449a in neuroblastoma has not been intensively investigated. We recently found that the overexpression of miR-449a significantly induces neuroblastoma cell differentiation, suggesting its potential tumor suppressor function in neuroblastoma. In this study, we further investigated the mechanisms underlying the tumor suppressive function of miR-449a in neuroblastoma. We observed that miR-449a inhibits neuroblastoma cell survival and growth through 2 mechanisms--inducing cell differentiation and cell cycle arrest. Our comprehensive investigations on the dissection of the target genes of miR-449a revealed that 3 novel targets- MFAP4, PKP4 and TSEN15 -play important roles in mediating its differentiation-inducing function. In addition, we further found that its function in inducing cell cycle arrest involves down-regulating its direct targets CDK6 and LEF1. To determine the clinical significance of the miR-449a-mediated tumor suppressive mechanism, we examined the correlation between the expression of these 5 target genes in neuroblastoma tumor specimens and the survival of neuroblastoma patients. Remarkably, we noted that high tumor expression levels of all the 3 miR-449a target genes involved in regulating cell differentiation, but not the target genes involved in regulating cell cycle, are significantly correlated with poor survival of neuroblastoma patients. These results suggest the critical role of the differentiation-inducing function of miR-449a in determining neuroblastoma progression. Overall, our study provides the first comprehensive characterization of the tumor-suppressive function of miR-449a in neuroblastoma, and reveals the potential clinical significance of the miR-449a-mediated tumor suppressive pathway in neuroblastoma prognosis.

Zhang C, Fang X, Li W, et al.
Influence of recombinant lentiviral vector encoding miR-15a/16-1 in biological features of human nasopharyngeal carcinoma CNE-2Z cells.
Cancer Biother Radiopharm. 2014; 29(10):422-7 [PubMed] Related Publications
MicroRNAs can function as tumor suppressor miRNAs. Bcl-2 is an antiapoptotic gene overexpressed in many tumors, including nasopharyngeal carcinoma (NPC). It is reported that microRNA-15a (miR-15a) and microRNA-16-1 (miR-16-1) could act as bcl-2 inhibitors. To investigate their effects on NPC, the authors used recombinant lentiviral vector to upregulate the expression of miR-15a/16-1 in NPC CNE-2Z cells. The authors divided cells into the control group, transfection group, radiotherapy group, and transfection-radiotherapy group. In this experiment, reverse transcription-quantitative polymerase chain reaction was used to detect the expression of miR-15a/16-1 and bcl-2 mRNA. Cell proliferation was analyzed by MTT assay. Flow cytometry was used to measure cell apoptosis. Radiosensitivity was measured using colony-forming experiment. The protein expression of bcl-2 was measured by western blot, the activation levels of caspase were detected by a spectrophotometric method. After transfection, cell proliferation was inhibited, while the apoptosis rate and radiosensitivity were increased. In addition, the activation of caspase-2 and caspase-3 was aggrandized correspondingly. Although the expression levels of bcl-2 mRNA in each group had no difference, the protein expression of bcl-2 was downregulated. These results suggested that miR-15a/16-1 could inhibit cell proliferation and increase the apoptosis and radiosensitivity of CNE-2 cells, by regulating the bcl-2 gene at post-transcriptional level and by increasing the activation of caspase-2 and caspase-3.

Picco R, Tomasella A, Fogolari F, Brancolini C
Transcriptomic analysis unveils correlations between regulative apoptotic caspases and genes of cholesterol homeostasis in human brain.
PLoS One. 2014; 9(10):e110610 [PubMed] Free Access to Full Article Related Publications
Regulative circuits controlling expression of genes involved in the same biological processes are frequently interconnected. These circuits operate to coordinate the expression of multiple genes and also to compensate dysfunctions in specific elements of the network. Caspases are cysteine-proteases with key roles in the execution phase of apoptosis. Silencing of caspase-2 expression in cultured glioblastoma cells allows the up-regulation of a limited number of genes, among which some are related to cholesterol homeostasis. Lysosomal Acid Lipase A (LIPA) was up-regulated in two different cell lines in response to caspase-2 down-regulation and cells silenced for caspase-2 exhibit reduced cholesterol staining in the lipid droplets. We expanded this observation by large-scale analysis of mRNA expression. All caspases were analyzed in terms of co-expression in comparison with 166 genes involved in cholesterol homeostasis. In the brain, hierarchical clustering has revealed that the expression of regulative apoptotic caspases (CASP2, CASP8 CASP9, CASP10) and of the inflammatory CASP1 is linked to several genes involved in cholesterol homeostasis. These correlations resulted in altered GBM (Glioblastoma Multiforme), in particular for CASP1. We have also demonstrated that these correlations are tissue specific being reduced (CASP9 and CASP10) or different (CASP2) in the liver. For some caspases (CASP1, CASP6 and CASP7) these correlations could be related to brain aging.

Terry MR, Arya R, Mukhopadhyay A, et al.
Caspase-2 impacts lung tumorigenesis and chemotherapy response in vivo.
Cell Death Differ. 2015; 22(5):719-30 [PubMed] Free Access to Full Article Related Publications
Caspase-2 is an atypical caspase that regulates apoptosis, cell cycle arrest and genome maintenance, although the mechanisms are not well understood. Caspase-2 has also been implicated in chemotherapy response in lung cancer, but this function has not been addressed in vivo. Here we show that Caspase-2 functions as a tumor suppressor in Kras-driven lung cancer in vivo. Loss of Caspase-2 leads to enhanced tumor proliferation and progression. Despite being more histologically advanced, Caspase-2-deficient tumors are sensitive to chemotherapy and exhibit a significant reduction in tumor volume following repeated treatment. However, Caspase-2-deficient tumors rapidly rebound from chemotherapy with enhanced proliferation, ultimately hindering long-term therapeutic benefit. In response to DNA damage, Caspase-2 cleaves and inhibits Mdm2 and thereby promotes the stability of the tumor-suppressor p53. Caspase-2 expression levels are significantly reduced in human lung tumors with wild-type p53, in agreement with the model whereby Caspase-2 functions through Mdm2/p53 regulation. Consistently, p53 target genes including p21, cyclin G1 and Msh2 are reduced in Caspase-2-deficient tumors. Finally, we show that phosphorylation of p53-induced protein with a death domain 1 leads to Caspase-2-mediated cleavage of Mdm2, directly impacting p53 levels, activity and chemotherapy response. Together, these studies elucidate a Caspase-2-p53 signaling network that impacts lung tumorigenesis and chemotherapy response in vivo.

Dorstyn L, Puccini J, Nikolic A, et al.
An unexpected role for caspase-2 in neuroblastoma.
Cell Death Dis. 2014; 5:e1383 [PubMed] Free Access to Full Article Related Publications
Caspase-2 has been implicated in various cellular functions, including cell death by apoptosis, oxidative stress response, maintenance of genomic stability and tumor suppression. The loss of the caspase-2 gene (Casp2) enhances oncogene-mediated tumorigenesis induced by E1A/Ras in athymic nude mice, and also in the Eμ-Myc lymphoma and MMTV/c-neu mammary tumor mouse models. To further investigate the function of caspase-2 in oncogene-mediated tumorigenesis, we extended our studies in the TH-MYCN transgenic mouse model of neuroblastoma. Surprisingly, we found that loss of caspase-2 delayed tumorigenesis in the TH-MYCN neuroblastoma model. In addition, tumors from TH-MYCN/Casp2(-/-) mice were predominantly thoracic paraspinal tumors and were less vascularized compared with tumors from their TH-MYCN/Casp2(+/+) counterparts. We did not detect any differences in the expression of neuroblastoma-associated genes in TH-MYCN/Casp2(-/-) tumors, or in the activation of Ras/MAPK signaling pathway that is involved in neuroblastoma progression. Analysis of expression array data from human neuroblastoma samples showed a correlation between low caspase-2 levels and increased survival. However, caspase-2 levels correlated with clinical outcome only in the subset of MYCN-non-amplified human neuroblastoma. These observations indicate that caspase-2 is not a suppressor in MYCN-induced neuroblastoma and suggest a tissue and context-specific role for caspase-2 in tumorigenesis.

Winkler C, Doller A, Imre G, et al.
Attenuation of the ELAV1-like protein HuR sensitizes adenocarcinoma cells to the intrinsic apoptotic pathway by increasing the translation of caspase-2L.
Cell Death Dis. 2014; 5:e1321 [PubMed] Free Access to Full Article Related Publications
Caspase-2 represents the most conserved member of the caspase family, which exhibits features of both initiator and effector caspases. Using ribonucleoprotein (RNP)-immunoprecipitation assay, we identified the proapoptotic caspase-2L encoding mRNA as a novel target of the ubiquitous RNA-binding protein HuR in DLD-1 colon carcinoma cells. Unexpectedly, crosslinking-RNP and RNA probe pull-down experiments revealed that HuR binds exclusively to the caspase-2-5' untranslated region (UTR) despite that the 3' UTR of the mRNA bears several adenylate- and uridylate-rich elements representing the prototypical HuR binding sites. By using RNAi-mediated loss-of-function approach, we observed that HuR regulates the mRNA and in turn the protein levels of caspase-2 in a negative manner. Silencing of HuR did not affect the stability of caspase-2 mRNA but resulted in an increased redistribution of caspase-2 transcripts from RNP particles to translational active polysomes implicating that HuR exerts a direct repressive effect on caspase-2 translation. Consistently, in vitro translation of a luciferase reporter gene under the control of an upstream caspase-2-5'UTR was strongly impaired after the addition of recombinant HuR, whereas translation of caspase-2 coding region without the 5'UTR is not affected by HuR confirming the functional role of the caspase-2-5'UTR. Functionally, an elevation in caspase-2 level by HuR knockdown correlated with an increased sensitivity of cells to apoptosis induced by staurosporine- and pore-forming toxins as implicated by their significant accumulation in the sub G1 phase and an increase in caspase-2, -3 and poly ADP-ribose polymerase cleavage, respectively. Importantly, HuR knockdown cells remained insensitive toward STS-induced apoptosis if cells were additionally transfected with caspase-2-specific siRNAs. Collectively, our findings support the hypothesis that HuR by acting as an endogenous inhibitor of caspase-2-driven apoptosis may essentially contribute to the antiapoptotic program of adenocarcinoma cells by HuR.

Zhang Q, Hu H, Shi X, Tang W
Knockdown of S100P by lentiviral-mediated RNAi promotes apoptosis and suppresses the colony-formation ability of gastric cancer cells.
Oncol Rep. 2014; 31(5):2344-50 [PubMed] Related Publications
S100P is a putative candidate oncogene in several types of human tumors. However, expression of S100P, its potential role and its clinical significance in gastric cancer remain unclear. In the present study, S100P expression was examined by immunohistochemistry using a tissue microarray. Positive staining for S100P was noted in 77.1% of the cases while 22.9% were negative. In two gastric cancer cell lines, MGC-803 and SGC-7901, S100P expression was knocked down by a lentiviral short hairpin delivery system. The RNA interference-mediated downregulation of S100P expression markedly promoted cell apoptosis and inhibited cell colony-formation ability of the gastric cancer cells. In addition, knockdown of S100P significantly regulated the expression of 12 apoptosis-associated genes with a >1.5-fold change compared with the negative control. Among them, FOS, DDIT3 and FN1 were significantly upregulated, while FASLG, DAPK1, CTNNB1 and CASP2 were notably downregulated following S100P silencing. These results suggest that S100P acts as an oncogenic factor in gastric cancer and is a potential molecular target for gastric cancer gene therapy.

Mfouo-Tynga I, Houreld NN, Abrahamse H
Induced cell death pathway post photodynamic therapy using a metallophthalocyanine photosensitizer in breast cancer cells.
Photomed Laser Surg. 2014; 32(4):205-11 [PubMed] Related Publications
OBJECTIVE: Zinc phthalocyanine (ZnPcSmix) was used as the photosensitizer (PS) in this study to investigate the cell death patterns as a result of photodynamic therapy (PDT) in a breast cancer cell line (MCF-7) in vitro using a 680 nm diode laser at a fluence of 5 J/cm(2).
BACKGROUND: PDT is a noninvasive form of cancer therapy, successfully applied for the treatment of various cancer types.
METHODS: Flow cytometry using Annexin V-fluorescein isothiocyanate (FITC), a cell death immunosorbent assay (ELISA), and gene expression analysis following ZnPcSmix mediated PDT were performed to determine the induced cell death pathways.
RESULTS: The apoptotic cells abounded after the treatment, nuclear fragmentation was seen as oligonucleosomal degradation and increased expression of the B-cell lymphoma 2 (Bcl-2), DNA fragmentation factor alpha (DFFA1), and caspase 2 (CASP2) genes, indicated that apoptosis is the main induced mode of cell death.
CONCLUSIONS: ZnPcSmix mediated PDT led to an apoptotic cell death pathway and the PS used showed its ability to stimulate and initiate programmed cell death.

Han C, Zhao R, Kroger J, et al.
Caspase-2 short isoform interacts with membrane-associated cytoskeleton proteins to inhibit apoptosis.
PLoS One. 2013; 8(7):e67033 [PubMed] Free Access to Full Article Related Publications
Caspase-2 (casp-2) is the most conserved caspase across species, and is one of the initiator caspases activated by various stimuli. The casp-2 gene produces several alternative splicing isoforms. It is believed that the long isoform, casp-2L, promotes apoptosis, whereas the short isoform, casp-2S, inhibits apoptosis. The actual effect of casp-2S on apoptosis is still controversial, however, and the underlying mechanism for casp-2S-mediated apoptosis inhibition is unclear. Here, we analyzed the effects of casp-2S on DNA damage induced apoptosis through "gain-of-function" and "loss-of-function" strategies in ovarian cancer cell lines. We clearly demonstrated that the over-expression of casp-2S inhibited, and the knockdown of casp-2S promoted, the cisplatin-induced apoptosis of ovarian cancer cells. To explore the mechanism by which casp-2S mediates apoptosis inhibition, we analyzed the proteins which interact with casp-2S in cells by using immunoprecipitation (IP) and mass spectrometry. We have identified two cytoskeleton proteins, Fodrin and α-Actinin 4, which interact with FLAG-tagged casp-2S in HeLa cells and confirmed this interaction through reciprocal IP. We further demonstrated that casp-2S (i) is responsible for inhibiting DNA damage-induced cytoplasmic Fodrin cleavage independent of cellular p53 status, and (ii) prevents cisplatin-induced membrane blebbing. Taken together, our data suggests that casp-2S affects cellular apoptosis through its interaction with membrane-associated cytoskeletal Fodrin protein.

Zhu Y, Li Y, Haraguchi S, et al.
Dependence receptor UNC5D mediates nerve growth factor depletion-induced neuroblastoma regression.
J Clin Invest. 2013; 123(7):2935-47 [PubMed] Free Access to Full Article Related Publications
Spontaneous regression of neuroblastoma (NB) resembles the developmentally regulated programmed cell death (PCD) of sympathetic neurons. Regressing tumor cells express high levels of the nerve growth factor (NGF) receptors TRKA and p75NTR and are dependent on NGF for survival; however, the underlying molecular mechanism remains elusive. Here, we show that UNC5D, a dependence receptor that is directly targeted by p53 family members, is highly expressed in favorable NBs. NGF withdrawal strongly upregulated UNC5D, E2F1, and p53 in human primary favorable NBs. The induced UNC5D was cleaved by caspases 2/3, and the released intracellular fragment translocated into the nucleus and interacted with E2F1 to selectively transactivate the proapoptotic target gene. The cleavage of UNC5D and its induction of apoptosis were strongly inhibited by addition of netrin-1. Unc5d(-/-) mice consistently exhibited a significant increase in dorsal root ganglia neurons and resistance to NGF depletion-induced apoptosis in sympathetic neurons compared with wild-type cells. Our data suggest that UNC5D forms a positive feedback loop with p53 and E2F1 to promote NGF dependence-mediated PCD during NB regression.

Song T, Zhang X, Zhang L, et al.
miR-708 promotes the development of bladder carcinoma via direct repression of Caspase-2.
J Cancer Res Clin Oncol. 2013; 139(7):1189-98 [PubMed] Related Publications
PURPOSE: Bladder cancer is one of the world's top ten malignant tumors. The crucial role of microRNA in carcinogenesis has been well emphasized. Considering miRNA expression was tumor stage-, tissue-, or even development-specific, more experimental evidences about the functions of miRNAs in bladder cancer should be discovered to advance applying of miRNA in the diagnosis or therapy of cancer.
METHODS: MiR-708 level in bladder carcinoma and adjacent noncancerous tissues was tested by real-time qPCR. Cell apoptosis was analyzed by using flow cytometry. The tumorigenicity of bladder carcinoma cells was evaluated in nude mice model. Luciferase reporter gene assays were performed to identify the interaction between miR-708 and 3'UTR of Caspase-2 mRNA. The protein level of Caspase-2 was determined by western blotting.
RESULTS: In this study, we reported that miR-708 was frequently dysregulated in human bladder carcinoma tissues compared to normal tissues. In addition, we found that silencing of miR-708 could promote the T24 and 5637 cells to apoptosis and inhibit the bladder tumor growth in vivo. Also, Caspase-2 was proved to be one of direct targets of miR-708 in T24 and 5637 cells. Further results showed that Caspase-2 was involved in the miR-708 regulated cell apoptosis.
CONCLUSIONS: All together, these results suggest miR-708 may act as an oncogene and induce the carcinogenicity of bladder cancer by down-regulating Caspase-2 level.

Ehrlichova M, Mohelnikova-Duchonova B, Hrdy J, et al.
The association of taxane resistance genes with the clinical course of ovarian carcinoma.
Genomics. 2013; 102(2):96-101 [PubMed] Related Publications
Taxane and platinum-based chemotherapy regimens are standard treatment for advanced ovarian carcinoma. Expression levels of putative markers of taxane resistance in carcinoma tissues and paired peritoneal samples (n=55) and in 16 samples of ovaries without signs of carcinoma were compared with clinical data and the patients' time to progression. KIF14, PRC1, CIT and ABCC1 genes were significantly overexpressed in carcinomas when compared with normal ovarian tissues, while ABCB1 and CASP9 expression was decreased. Associations of protein expression of the proliferation marker Ki-67 with KIF14, PRC1, ABCB1 and CASP2 were found. Lastly, it was discovered that ABCB1 and CASP2 levels associated with FIGO stage and that the CIT level associated with the time to progression of ovarian carcinoma patients (P<0.0001). In conclusion, ABCB1, CASP2, KIF14, PRC1 and CIT genes seem to associate with surrogate markers of ovarian carcinoma progression and CIT gene associates with therapy outcome.

Brynychová V, Hlaváč V, Ehrlichová M, et al.
Importance of transcript levels of caspase-2 isoforms S and L for breast carcinoma progression.
Future Oncol. 2013; 9(3):427-38 [PubMed] Related Publications
AIM: A role of caspase-2 in chemotherapy-induced apoptosis has been suggested. Our study aimed to evaluate the prognostic and predictive importance of caspase-2 isoforms in breast cancer patients.
MATERIALS & METHODS: Caspase-2L and -2S transcript levels were determined in paired tumor and non-malignant control tissues from 64 patients after neoadjuvant chemotherapy and 100 pretreatment patients (general set) by real-time PCR with absolute quantification.
RESULTS: Low but statistically significant upregulation of caspase-2L in tumor versus control tissues was observed in both sets. Significant associations of the levels of caspase-2L, -2S or S/L ratio with clinical prognostic factors were observed. However, none of these associations were confirmed in both sets. Levels of caspase-2 isoforms or the S/L ratio did not significantly associate with progression-free survival in the general set or with chemotherapy response in the neoadjuvant set.
CONCLUSION: Our results suggest that the role of caspase-2 isoforms in the progression of breast cancer may considerably differ between pre- and post-chemotherapy patients.

Huang Y, Chuang AY, Ratovitski EA
Phospho-ΔNp63α/miR-885-3p axis in tumor cell life and cell death upon cisplatin exposure.
Cell Cycle. 2011; 10(22):3938-47 [PubMed] Free Access to Full Article Related Publications
The cisplatin-induced ATM-dependent phosphorylated (p)-ΔNp63α plays an important role in transcriptional regulation of specific genes encoding mRNAs and microRNAs (miRs) implicated in cell death, cell survival, and chemoresistance. The p-ΔNp63α-induced miR-885-3p functions as a critical regulator of MDM4, ATK1, BCL2, ATG16L2, ULK2, CASP2, and CASP3 mRNAs via pairing with their respective 'recognition' sequences. Cisplatin exposure modulated the levels of target proteins (reduced BCL2, AKT1, ATG16L2, and ULK2, while activated MDM4) in cisplatin-sensitive wild type ΔNp63α cells leading to distinct changes in cell viability. Finally, miR-885-3p modulated the cisplatin-induced TP53-dependent mitochondrial apoptosis by up regulation of MDM4 levels and down regulation of BCL2 levels in mitochondria. Altogether, our results support the notion that miR-885-3p might contribute in regulation of cell viability, apoptosis and/or autophagy in squamous cell carcinoma cells upon cisplatin exposure.

Yoo BH, Wang Y, Erdogan M, et al.
Oncogenic ras-induced down-regulation of pro-apoptotic protease caspase-2 is required for malignant transformation of intestinal epithelial cells.
J Biol Chem. 2011; 286(45):38894-903 [PubMed] Free Access to Full Article Related Publications
Resistance of carcinoma cells to anoikis, apoptosis that is normally induced by loss of cell-to-extracellular matrix adhesion, is thought to be essential for the ability of these cells to form primary tumors, invade adjacent tissues, and metastasize to distant organs. Current knowledge about the mechanisms by which cancer cells evade anoikis is far from complete. In an effort to understand these mechanisms, we found that ras, a major oncogene, down-regulates protease caspase-2 (which initiates certain steps of the cellular apoptotic program) in malignant human and rat intestinal epithelial cells. This down-regulation could be reversed by inhibition of a protein kinase Mek, a mediator of Ras signaling. We also found that enforced down-regulation of caspase-2 in nonmalignant intestinal epithelial cells by RNA interference protected them from anoikis. Furthermore, the reversal of the effect of Ras on caspase-2 achieved by the expression of exogenous caspase-2 in detached ras-transformed intestinal epithelial cells promoted well established apoptotic events, such as the release of the pro-apoptotic mitochondrial factors cytochrome c and HtrA2/Omi into the cytoplasm of these cells, significantly enhanced their anoikis susceptibility, and blocked their long term growth in the absence of adhesion to the extracellular matrix. Finally, the blockade of the effect of Ras on caspase-2 substantially suppressed growth of tumors formed by the ras-transformed cells in mice. We conclude that ras-induced down-regulation of caspase-2 represents a novel mechanism by which oncogenic Ras protects malignant intestinal epithelial cells from anoikis, promotes their anchorage-independent growth, and allows them to form tumors in vivo.

Lamers F, van der Ploeg I, Schild L, et al.
Knockdown of survivin (BIRC5) causes apoptosis in neuroblastoma via mitotic catastrophe.
Endocr Relat Cancer. 2011; 18(6):657-68 [PubMed] Related Publications
BIRC5 (survivin) is one of the genes located on chromosome arm 17q in the region that is often gained in neuroblastoma. BIRC5 is a protein in the intrinsic apoptotic pathway that interacts with XIAP and DIABLO leading to caspase-3 and caspase-9 inactivation. BIRC5 is also involved in stabilizing the microtubule-kinetochore dynamics. Based on the Affymetrix mRNA expression data, we here show that BIRC5 expression is strongly upregulated in neuroblastoma compared with normal tissues, adult malignancies, and non-malignant fetal adrenal neuroblasts. The over-expression of BIRC5 correlates with an unfavorable prognosis independent of the presence of 17q gain. Silencing of BIRC5 in neuroblastoma cell lines by various antisense molecules resulted in massive apoptosis as measured by PARP cleavage and FACS analysis. As both the intrinsic apoptotic pathway and the chromosomal passenger complex can be therapeutically targeted, we investigated in which of them BIRC5 exerted its essential anti-apoptotic role. Immunofluorescence analysis of neuroblastoma cells after BIRC5 silencing showed formation of multinucleated cells indicating mitotic catastrophe, which leads to apoptosis via P53 and CASP2. We show that BIRC5 silencing indeed resulted in activation of P53 and we could rescue apoptosis by CASP2 inhibition. We conclude that BIRC5 stabilizes the microtubules in the chromosomal passenger complex in neuroblastoma and that the apoptotic response results from mitotic catastrophe, which makes BIRC5 an interesting target for therapy.

Ulybina YM, Kuligina ES, Mitiushkina NV, et al.
Distribution of coding apoptotic gene polymorphisms in women with extreme phenotypes of breast cancer predisposition and tolerance.
Tumori. 2011 Mar-Apr; 97(2):248-51 [PubMed] Related Publications
AIMS AND BACKGROUND: Comparison of subjects with extreme phenotypes of cancer susceptibility and tolerance allows to detect low-penetrance gene-disease interactions with a relatively small study size.
METHODS AND STUDY DESIGN: We analyzed the distribution of 19 coding apoptotic gene polymorphisms (Bid Gly10Ser; Casp2 Leu141Val; Casp5 Ala90Thr and Val318Leu; Casp7 Glu255Asp; Casp8 His302Asp; Casp9 Val28Ala, His173Arg and Arg221Gln; Casp10 Ile479Leu; Faim Thr117Ala and Ser127Leu; DR4 Arg141His, Thr209Arg, Ala228Glu and Lys441Arg; Survivin Lys129Glu; TNFR1 Gln121Arg; XIAP Pro423Gln) in 121 breast cancer patients with clinical features of a hereditary predisposition (family history and/or early onset and/or bilaterality) and 142 elderly tumor-free women.
RESULTS: None of the individual single nucleotide polymorphisms (SNPs) demonstrated an association with breast cancer risk. The analysis of gene interactions revealed that the combination of XIAP Pro423Gln (rs5956583) AA genotype with Casp7 Glu255Asp (rs2227310) CG genotype appeared to prevail in "supercases" relative to "supercontrols" (25/121 [21%] vs 11/142 [8%], P = 0.002). We attempted to validate this association in the second round of case-control analysis, which involved 519 randomly selected breast cancer patients and 509 age-matched healthy women, but no difference was detected upon this comparison.
CONCLUSIONS: Coding apoptotic gene polymorphisms do not play a major role in BC predisposition. The results of this investigation may be considered while designing future studies on breast cancer-associated candidate SNPs.

Seo HW, Rengaraj D, Choi JW, et al.
The expression profile of apoptosis-related genes in the chicken as a human epithelial ovarian cancer model.
Oncol Rep. 2011; 25(1):49-56 [PubMed] Related Publications
The purpose of our study was to examine the expression pattern of apoptosis-related genes in normal and cancerous ovaries of the hen. Localization of apoptosis-related gene mRNA was investigated in cancerous ovaries using in situ hybridization. The expression patterns of apoptosis-related genes were confirmed with RT-PCR in normal and cancerous ovaries. Differences of expression level between normal ovaries and ovarian cancers were analyzed using quantitative RT-PCR. In both normal and cancerous chicken ovaries, the expression of CASP1, CASP2, CASP3, CASP6, CASP8 and CASP9 were detected through RT-PCR analysis. The expression of BCL2, BCL2L1 and BID were confirmed in normal and cancerous ovaries of the hen. Quantitative RT-PCR showed that CASP1 expression was significantly increased in cancerous ovaries compared with normal ovaries, whereas BID expression was decreased. Our results showed a resistance to removal of abnormal cells via apoptosis in cancerous ovaries of the hen. Collectively, this phenomenon is closely associated with the dysregulation of CASP1 and BID expression in chicken ovarian cancer.

Babas E, Ekonomopoulou MT, Karapidaki I, et al.
Indication of participation of caspase-2 and caspase-5 in mechanisms of human cervical malignancy.
Int J Gynecol Cancer. 2010; 20(8):1381-5 [PubMed] Related Publications
INTRODUCTION: When apoptosis is disrupted, the transformed cells can survive, proliferate, and evolve into a malignancy. The strictly conserved caspase genes and the reliable experimental data clearly show that some caspases play a crucial role in apoptosis even if some of them have no apoptotic activity and others exhibit both apoptotic and nonapoptotic properties. Although caspase-2 belongs to initiator caspases, its normal role remains unclear. Experimental studies have shown that it is primarily necessary for the execution of apoptosis in mutagenic cells. Human caspase-5 is classified as an inflammatory caspase, although its substrate has not been identified yet. In this research, the activities of caspase-2 and caspase-5 have been estimated during the progression of human cervical malignancy.
METHODS: The experimental material includes human cervical tissue samples (normal and pathological) and blood serum samples of the corresponding tissue donors, where enzyme activities have been measured colorimetrically.
RESULTS: Both caspases' activities showed the highest increase, statistically significant (P < 0.01, by t test) compared with the controls, in the low-grade squamous intraepithelial lesion tissues. Caspase-2 of all pathological tissues was proved more active than the controls. Serum caspases' activities were significantly lower than those of the tissues. Serum caspase-2's activity in patients with low-grade squamous intraepithelial lesion stage showed no statistically significant increase compared with the controls. Serum caspase-5's activity of all patients with malignancy stages was presented elevated, whereas that of the serum of patients with cervical cancer had the highest activity (P < 0.01, by t test).
CONCLUSIONS: The changes of caspase-2 and caspase-5 activities could be indicative of their involvement in the cervical malignancy mechanisms.

Yan J, Katz AE
ProstaCaid induces G2/M cell cycle arrest and apoptosis in human and mouse androgen-dependent and-independent prostate cancer cells.
Integr Cancer Ther. 2010; 9(2):186-96 [PubMed] Related Publications
The anticancer effects of ProstaCaid, a novel integrative blend of vitamins, minerals, multiherb extracts, and derivatives, were tested in human and mouse androgen-dependent (AD) and -independent (AI) prostate cancer cell lines. ProstaCaid shows growth inhibitory effects on both human and mouse AD prostate cancer cells (LNCaP and CASP 2.1) and AI prostate cancer cells (PC3 and CASP 1.1) in a dose-/time-dependent manner. Consistently, long-term treatment with ProstaCaid also reduced colony formation capacities of prostate cancer cells. Flow cytometry assays revealed that ProstaCaid induces G2/M arrest and apoptosis in LNCaP and PC3 cells after 72 hours of treatment. Immunoblotting assay demonstrated that 25 microg/mL of ProstaCaid treatment resulted in (1) the reduction of cyclin D1, cyclin B1, and Cdc2 expression in a time-dependent way; (2) increase in p21(WAF1/Cip1) as early as 12 hours after the treatments in PC3 cells and reduction to base line at the 72-hour time point; and (3) repression of Bcl-2, BclxL, and induction of Bim as well as the cleavages of caspase-3 and poly(ADP-ribose) polymerase (PARP) at 72 hours of treatment, suggesting caspase-3-dependent apoptosis. Moreover, ProstaCaid suppressed activation of AKT and MAPK signaling pathways in PC3 and LNCaP cells by reducing phosphorylation levels of AKT, its downstream target S6 ribosomal protein and GSK3beta, and ERK1/2, respectively. In summary, these findings strongly suggest that ProstaCaid may be a potential chemopreventive and therapeutic agent for both AD and, more importantly, AI prostate cancer.

Yan J, Katz A
PectaSol-C modified citrus pectin induces apoptosis and inhibition of proliferation in human and mouse androgen-dependent and- independent prostate cancer cells.
Integr Cancer Ther. 2010; 9(2):197-203 [PubMed] Related Publications
AIM: To demonstrate the efficacy of PectaSol-C modified citrus pectin (MCP) on prostate cancer in vitro.
METHOD: Cytotoxicity analysis of PectaSol-C was performed by MTT assay, as were parallel studies with the former brand version of MCP called PectaSol. Apoptosis and inhibition of cell growth were investigated by Western blotting.
RESULTS: Androgen-dependent and -independent human prostate cancer cell lines (LNCaP and PC3, respectively), androgen-dependent and -independent murine prostate cancer cell lines (CASP2.1 and CASP1.1, respectively), as well as noncancerous human benign prostate hyperplasia BPH-1 cell line, were used in the study. MTT assay revealed that 1.0% PectaSol exerted cytotoxicity on LNCaP, PC3, CASP2.1, CASP1.1, and BPH-1 cells for 4-day treatment by 48.0% +/- 2.1%, 54.4% +/- 0.3%, 15.4% +/- 0.8%, 46.1% +/- 1.7%, and 27.4% +/- 1.6%, respectively; whereas 1.0% PectaSol-C showed cytotoxity by 52.2% +/- 1.8%, 48.2% +/- 2.9%, 23.0% +/- 2.6%, 49.0% +/- 1.3%, and 26.8% +/- 2.6%, respectively. Western blotting further confirmed that both MCPs inhibit MAP kinase activation, increase the expression level of its downstream target Bim, a pro-apoptotic protein, and induce the cleavage of Caspase-3 in PC3 and CASP1.1 prostate cancer cells.
CONCLUSION: PectaSol MCP and PectaSol-C MCP can inhibit cell proliferation and apoptosis in prostate cancer cell lines. Our data suggested that 1.0% PectaSol-C can be used for further chemopreventive and chemotherapeutic analysis in vivo.

Glinskii AB, Glinsky GV, Lin HY, et al.
Modification of survival pathway gene expression in human breast cancer cells by tetraiodothyroacetic acid (tetrac).
Cell Cycle. 2009; 8(21):3562-70 [PubMed] Related Publications
Tetraiodothyroacetic acid (tetrac) inhibits the cellular actions of thyroid hormone initiated at the hormone receptor on plasma membrane integrin alphavbeta3. Via interaction with the integrin, tetrac is also capable of inhibiting the angiogenic effects of vascular endothelial growth factor and basic fibroblast growth factor. MDA-MB-231 cells are estrogen receptor-negative human breast cancer cells shown to be responsive to tetrac in terms of decreased cell proliferation. Here we describe actions initiated at the cell surface receptor by unmodified tetrac and nanoparticulate tetrac on a panel of survival pathway genes in estrogen receptor-negative human breast cancer (MDA-MB-231) cells. Nanoparticulate tetrac is excluded from the cell interior. Expression of apoptosis inhibitors XIAP (X-linked inhibitor of apoptosis) and MCL1 (myeloid cell leukemia sequence 1) was downregulated by nanoparticulate tetrac in these breast cancer cells whereas apoptosis-promoting CASP2 and BCL2L14 were upregulated by the nanoparticulate formulation. Unmodified tetrac affected only XIAP expression. Expression of the angiogenesis inhibitor thrombospondin 1 (THBS1) gene was increased by both formulations of tetrac, as was the expression of CBY1, a nuclear inhibitor of catenin activity. The majority of differentially regulated Ras-oncogene family members were downregulated by nanoparticulate tetrac. The latter downregulated expression of epidermal growth factor receptor gene and unmodified tetrac did not. Nanoparticulate tetrac has coherent anti-cancer actions on expression of differentially-regulated genes important to survival of MDA-MB-231 cells.

Pan Y, Ren KH, He HW, Shao RG
Knockdown of Chk1 sensitizes human colon carcinoma HCT116 cells in a p53-dependent manner to lidamycin through abrogation of a G2/M checkpoint and induction of apoptosis.
Cancer Biol Ther. 2009; 8(16):1559-66 [PubMed] Related Publications
Recent advances in cell cycle regulation have led to a suggestion of therapeutically targeting cell cycle checkpoint pathways in cancer cells to increase the toxicity of DNA-damaging agents. In this study, we investigate whether knockdowns of checkpoint kinases Chk1 and Chk2 by RNA interfering potentiate the cytotoxicity and abrogate G(2)/M checkpoint induced by DNA-damaging agent lidamycin (LDM) in HCT116 cells with different p53 status. Our results showed that Chk1 knockdown enhanced the cytotoxicity of LDM through abrogating G(2)/M arrest and increasing apoptosis to a greater extent in HCT116 p53(-/-) cells than in p53(wt) cells. Abrogation of LDM-induced G(2)/M arrest by Chk1 knockdown was associated with reducing the inactivated phosphorylations of Cdc25C and Cdc2. LDM-induced gamma-H2AX was increased in cells with Chk1 knockdown, indicating that DNA double-strand breaks (DSBs) were enhanced. Furthermore, knockdown of Chk1 also increased LDM-mediated apoptotic cell death in p53 knockout cells with activation of caspase-2 and caspase-3. On the contrary, knockdown of Chk2 had no impact on G(2)/M arrest or apoptosis induced by LDM. Moreover, dual knockdown of Chk1 and Chk2 failed to achieve better efficacy than Chk1 alone. Taken together, we suggest that Chk1 is a potential therapeutic target to sensitize human p53 deficient cancer cells to LDM.

Su DM, Zhang Q, Wang X, et al.
Two types of human malignant melanoma cell lines revealed by expression patterns of mitochondrial and survival-apoptosis genes: implications for malignant melanoma therapy.
Mol Cancer Ther. 2009; 8(5):1292-304 [PubMed] Free Access to Full Article Related Publications
Human malignant melanoma has poor prognosis because of resistance to apoptosis and therapy. We describe identification of the expression profile of 1,037 mitochondria-focused genes and 84 survival-apoptosis genes in 21 malignant melanoma cell lines and 3 normal melanocyte controls using recently developed hMitChip3 cDNA microarrays. Unsupervised hierarchical clustering analysis of 1,037 informative genes, and 84 survival-apoptosis genes, classified these malignant melanoma cell lines into type A (n = 12) and type B (n = 9). Three hundred fifty-five of 1,037 (34.2%) genes displayed significant (P ≤ 0.030; false discovery rate ≤ 3.68%) differences (± ≥ 2.0-fold) in average expression, with 197 genes higher and 158 genes lower in type A than in type B. Of 84 genes with known survival-apoptosis functions, 38 (45.2%) displayed the significant (P < 0.001; false discovery rate < 0.15%) difference. Antiapoptotic (BCL2, BCL2A1, PPARD, and RAF1), antioxidant (MT3, PRDX5, PRDX3, GPX4, GLRX2, and GSR), and proapoptotic (BAD, BNIP1, APAF1, BNIP3L, CASP7, CYCS, CASP1, and VDAC1) genes expressed at higher levels in type A than in type B, whereas the different set of antiapoptotic (PSEN1, PPP2CA, API5, PPP2R1B, PPP2R1A, and FIS1), antioxidant (HSPD1, GSS, SOD1, ATOX1, and CAT), and proapoptotic (ENDOG, BAK1, CASP2, CASP4, PDCD5, HTRA2, SEPT4, TNFSF10, and PRODH) genes expressed at lower levels in type A than in type B. Microarray data were validated by quantitative reverse transcription-PCR. These results showed the presence of two types of malignant melanoma, each with a specific set of dysregulated survival-apoptosis genes, which may prove useful for development of new molecular targets for therapeutic intervention and novel diagnostic biomarkers for treatment and prognosis of malignant melanoma.

Jourdan M, Reme T, Goldschmidt H, et al.
Gene expression of anti- and pro-apoptotic proteins in malignant and normal plasma cells.
Br J Haematol. 2009; 145(1):45-58 [PubMed] Free Access to Full Article Related Publications
The survival of malignant plasma cells is a key event in disease occurrence, progression and chemoresistance. Using DNA-microarrays, we analysed the expression of genes coding for 58 proteins linked with extrinsic and intrinsic apoptotic pathways, caspases and inhibitor of apoptosis proteins. We considered six memory B cells (MBC), seven plasmablasts (PPC), seven bone marrow plasma cells (BMPC) and purified myeloma cells (MMC) from 92 newly-diagnosed patients. Forty out of the 58 probe sets enabled the separation of MBC, PPC and BMPC in three homogeneous clusters, characterized by an elevated expression of TNFRSF10A, TNFRSF10B, BCL2A1, CASP8, CASP9 and PMAIP1 genes for MBC, of FAS, FADD, AIFM1, BIRC5, CASP CASP2, CASP3 and CASP6 for PPC and of BCL2, MCL1, BID, BIRC3 and XIAP for BMPC. Thus, B cell differentiation was associated with change of expression of pro-apoptotic and anti-apoptotic genes. Regarding MMC, the major finding was TRAIL upregulation that might be counteracted by a high osteoprotegerin production by BM stromal cells and a decreased expression of FAS, APAF1 and BNIP3 compared to normal BMPC. Out of the 40 genes, CASP2 and BIRC5 expression in MMC had adverse prognosis in two independent series of previously-untreated patients.

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