Research IndicatorsGraph generated 11 March 2017 using data from PubMed using criteria.
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 (3)
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).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: PIN1 (cancer-related)
In addition to oncogenic drivers, signaling nodes can critically modulate cancer-related cellular networks to strength tumor hallmarks. We identify G-protein-coupled receptor kinase 2 (GRK2) as a relevant player in breast cancer. GRK2 is up-regulated in breast cancer cell lines, in spontaneous tumors in mice, and in a proportion of invasive ductal carcinoma patients. Increased GRK2 functionality promotes the phosphorylation and activation of the Histone Deacetylase 6 (HDAC6) leading to de-acetylation of the Prolyl Isomerase Pin1, a central modulator of tumor progression, thereby enhancing its stability and functional interaction with key mitotic regulators. Interestingly, a correlation between GRK2 expression and Pin1 levels and de-acetylation status is detected in breast cancer patients. Activation of the HDAC6-Pin1 axis underlies the positive effects of GRK2 on promoting growth factor signaling, cellular proliferation and anchorage-independent growth in both luminal and basal breast cancer cells. Enhanced GRK2 levels promote tumor growth in mice, whereas GRK2 down-modulation sensitizes cells to therapeutic drugs and abrogates tumor formation. Our data suggest that GRK2 acts as an important onco-modulator by strengthening the functionality of key players in breast tumorigenesis such as HDAC6 and Pin1.
Bae JS, Noh SJ, Kim KM, et al.PIN1 in hepatocellular carcinoma is associated with TP53 gene status.
Oncol Rep. 2016; 36(4):2405-11 [PubMed
] Related Publications
Phosphorylation of proteins on serine/threonine residues that precede proline (pSer/Thr-Pro) is specifically catalyzed by the peptidyl-prolyl cis-trans isomerase PIN1. PIN1-mediated prolyl-isomerization induces cell cycle arrest and growth inhibition through the regulation of target proteins, including TP53. We examined whether PIN1 acts in a different manner according to TP53 gene status in hepatocellular carcinoma (HCC). We investigated the expression of PIN1 and TP53 proteins in 119 HCC tissue samples. We also analyzed PIN1 expression in combination with TP53 gene mutation and its correlation with the clinical outcome. In addition, we used synthetic small interfering RNA to silence PIN1 gene expression in TP53 wild-type and TP53 mutant HCC cell lines, and then evaluated cell proliferation, migration and invasion. Expression of PIN1 was strongly associated with expression of TP53 protein or TP53 mutation of HCC samples. PIN1 and TP53 expression in TP53 mutant HCC cell lines was higher than that in TP53 wild-type HCC cell lines. Silencing of PIN1 in HLE cells containing mutant TP53 significantly decreased cell proliferation, migration and invasion. In contrast to PIN1 silencing in HLE cells, PIN1 silencing in HepG2 cells containing functional wild-type TP53 resulted in enhanced tumor cell proliferation. HCC patients bearing PIN1 expression with wild-type TP53 were predicted to demonstrate favorable relapse-free survival. Our results suggest that PIN1 plays a role in cancer cell proliferation, migration and invasion in a different manner according to the TP53 gene mutation status in HCC. In particular, interaction of PIN1 with mutant TP53 can act as a tumor promoter and increase its oncogenic activities in HCC.
BACKGROUND: Opportunistic screening in hospitals is widely used to effectively reduce the incidence rate of cervical cancer in China and other developing countries. This study aimed to identify clinical risk factor algorithms that combine gynecologic examination and molecular testing (paired box gene 1 (PAX1) or zinc finger protein 582 (ZNF582) methylation or HPV16/18) results to improve diagnostic accuracy.
METHODS: The delta Cp of methylated PAX1 and ZNF582 was obtained via quantitative methylation-specific PCR in a training set (57 CIN2- and 43 cervical intraepithelial neoplasia ≥grade 3 (CIN3+) women), and the individual and combination gene sensitivities and specificities were determined. The detection accuracy of three algorithms combining gynecologic findings and genetic test results was then compared in a randomized case-control study comprising 449 women referred for colposcopic examination by gynecologists in the outpatient department of Xiangya Hospital between November 2011 and March 2013.
RESULTS: Significant association was observed between CIN3+ and methylated PAX1 or ZNF582 in combination with HPV16/18 (OR:15.52, 95 % CI:7.73-31.18). The sensitivities and specificities of methylated PAX1 or ZNF582 combined with HPV16/18 for CIN3+ women were 89.2 and 76.0 %, or 85.4 and 80.1 %, respectively. Of the three algorithms applied to cohort data and validated in the study, two indicated 100 % sensitivity in detecting cervical cancer and a low rate of referrals for colposcopy.
CONCLUSIONS: These algorithms might contribute to precise and objective cervical cancer diagnostics in the outpatient departments of hospitals in countries with high mortality and low screening rates or areas with uneven resource distribution.
Beretta GL, De Cesare M, Albano L, et al.Targeting peptidyl-prolyl isomerase pin1 to inhibit tumor cell aggressiveness.
Tumori. 2016 Mar-Apr; 102(2):144-9 [PubMed
] Related Publications
PURPOSE: Because the peptidyl-prolyl isomerase PIN1 interacts with multiple protein kinases and phosphoproteins into a network orchestrating the cellular response to various stimuli, there is an increasing interest in exploiting its potential as therapeutic target. In the present study, the effect of targeting PIN1 was investigated in 2 human cancer cell lines characterized by increased aggressive potential, high expression of erbB receptor family members, and defective p53.
METHODS: PIN1 silencing was carried out in skin squamous cell carcinoma A431 cells displaying elevated EGFR/HER1 levels and in ovarian adenocarcinoma SKOV-3 cells displaying high levels of erbB2 (HER2). Nonoverlapping siRNA duplexes targeting different regions of PIN1 mRNA were transfected in tumor cells, which were analyzed using Western blotting for the expression of selected proteins. In vivo tumorigenicity studies were carried out in athymic nude mice.
RESULTS: A431 and SKOV-3 cell systems were found to be a source of cells with increased aggressive potential, i.e., cancer stem cell-like cells, as defined by the capability to grow as spheres. A marked decrease of PIN1 levels and of sphere-forming capability was observed in PIN1-silenced cells. The expression of phospho-p38 decreased following PIN1 silencing in A431 and SKOV-3 cells, as well as phospho-EGFR levels in A431 - silenced cells. PIN1 inhibition prolonged latency and reduced tumor take and growth of SKOV-3 cells in nude mice.
CONCLUSIONS: Our results support that PIN1 may be a valuable target to hit in cancer cells characterized by increased aggressive potential, overexpression of erbB receptor family members, and defective p53.
Lattanzio F, Carboni L, Carretta D, et al.Treatment with the neurotoxic Aβ (25-35) peptide modulates the expression of neuroprotective factors Pin1, Sirtuin 1, and brain-derived neurotrophic factor in SH-SY5Y human neuroblastoma cells.
Exp Toxicol Pathol. 2016; 68(5):271-6 [PubMed
] Related Publications
The deposition of Amyloid β peptide plaques is a pathological hallmark of Alzheimer's disease (AD). The Aβ (25-35) peptide is regarded as the toxic fragment of full-length Aβ (1-42). The mechanism of its toxicity is not completely understood, along with its contribution to AD pathological processes. The aim of this study was to investigate the effect of the neurotoxic Aβ (25-35) peptide on the expression of the neuroprotective factors Pin1, Sirtuin1, and Bdnf in human neuroblastoma cells. Levels of Pin1, Sirtuin 1, and Bdnf were compared by real-time PCR and Western blotting in SH-SY5Y cells treated with Aβ (25-35) or administration vehicle. The level of Pin1 gene and protein expression was significantly decreased in cells exposed to 25 μM Aβ (25-35) compared to vehicle-treated controls. Similarly, Sirtuin1 expression was significantly reduced by Aβ (25-35) exposure. In contrast, both Bdnf mRNA and protein levels were significantly increased by Aβ (25-35) treatment, suggesting the activation of a compensatory response to the insult. Both Pin1 and Sirtuin 1 exert a protective role by reducing the probability of plaque deposition, since they promote amyloid precursor protein processing through non-amyloidogenic pathways. The present results show that Aβ (25-35) peptide reduced the production of these neuroprotective proteins, thus further increasing Aβ generation.
Wang T, Liu Z, Shi F, Wang JPin1 modulates chemo-resistance by up-regulating FoxM1 and the involvements of Wnt/β-catenin signaling pathway in cervical cancer.
Mol Cell Biochem. 2016; 413(1-2):179-87 [PubMed
] Related Publications
The prolyl isomerase Pin1, which is frequently highly expressed in many different cancers, can directly regulate cell proliferation and the cell cycle. However, the role of Pin1 in chemo-resistance remains to be elucidated in cervical cancer. The purpose of the present study was to investigate the role of Pin1 in the chemo-resistance of cervical cancer. The cisplatin resistance was assessed using the MTT assay. Pin1, FoxM1, β-catenin, Cyclin D1, and c-myc expression levels were detected by RT-qPCR or Western blot. The results showed that Pin1 expression displayed a similar expression pattern with the resistance to cisplatin in five cervical cell lines. Knockdown of Pin1 significantly increased the sensitivity to cisplatin in HeLa cells, while Pin1 overexpression decreased the sensitivity to cisplatin in Me180 cells. Knockdown of Pin1 significantly down-regulated FoxM1 expression in HeLa cells, while Pin1 overexpression showed a contrary effect in Me180 cells. Besides, overexpression of Pin1 markedly increased the protein expression of β-catenin and its target genes cyclin D1 and c-myc. FoxM1 siRNA remarkably reversed the promotory effect of pcDNA-Pin1(+) on β-catenin and its target genes cyclin D1 and c-myc in Me180 cells. Furthermore, we also found that FoxM1 siRNA and IWP-2 markedly decreased cell viability, and IWP-2 decreased cell viability to the maximum extent in the Me180 cells co-transfected with pcDNA-Pin1(+) and FoxM1 siRNA. Taken together, these data suggest that Pin1 contributes to cisplatin resistance, partly by up-regulating FoxM1 and Wnt/β-catenin signaling pathway involved in cervical cancer.
Peptidyl prolyl isomerase (PIN1) regulates the functional activity of a subset of phosphoproteins through binding to phosphorylated Ser/Thr-Pro motifs and subsequently isomerization of the phosphorylated bonds. Interestingly, PIN1 is overexpressed in many types of malignancies including breast, prostate, lung and colon cancers. However, its oncogenic functions have not been fully elucidated. Here, we report that PIN1 directly interacts with hypoxia-inducible factor (HIF)-1α in human colon cancer (HCT116) cells. PIN1 binding to HIF-1α occurred in a phosphorylation-dependent manner. We also found that PIN1 interacted with HIF-1α at both exogenous and endogenous levels. Notably, PIN1 binding stabilized the HIF-1α protein, given that their levels were significantly increased under hypoxic conditions. The stabilization of HIF-1α resulted in increased transcriptional activity, consequently upregulating expression of vascular endothelial growth factor, a major contributor to angiogenesis. Silencing of PIN1 or pharmacologic inhibition of its activity abrogated the angiogenesis. By utilizing a bioluminescence imaging technique, we were able to demonstrate that PIN1 inhibition dramatically reduced the tumor volume in a subcutaneous mouse xenograft model and angiogenesis as well as hypoxia-induced transcriptional activity of HIF-1α. These results suggest that PIN1 interacting with HIF-1α is a potential cancer chemopreventive and therapeutic target.
Sakuma Y, Nishikiori H, Hirai S, et al.Prolyl isomerase Pin1 promotes survival in EGFR-mutant lung adenocarcinoma cells with an epithelial-mesenchymal transition phenotype.
Lab Invest. 2016; 96(4):391-8 [PubMed
] Related Publications
The secondary epidermal growth factor receptor (EGFR) T790M mutation is the most prominent mechanism that confers resistance to first- or second-generation EGFR tyrosine kinase inhibitors (TKIs) in lung cancer treatment. Although third-generation EGFR TKIs can suppress the kinase activity of T790M-positive EGFR, they still cannot eradicate EGFR-mutated cancer cells. We previously reported that a subpopulation of EGFR-mutant lung adenocarcinomas depends on enhanced autophagy, instead of EGFR, for survival, and in this study we explore another mechanism that contributes to TKI resistance. We demonstrate here that an EGFR-mutant lung adenocarcinoma cell line, H1975 (L858R+T790M), has a subset of cells that exhibits an epithelial-mesenchymal transition (EMT) phenotype and can thrive in the presence of third-generation EGFR TKIs. These cells depend on not only autophagy but also on the isomerase Pin1 for survival in vitro, unlike their parental cells. The Pin1 protein was expressed in an EGFR-mutant lung cancer tissue that has undergone partial EMT and acquired resistance to EGFR TKIs, but not its primary tumor. These findings suggest that inhibition of Pin1 activity can be a novel strategy in lung cancer treatment.
Huang L, Mo Z, Lao X, et al.PIN1 genetic polymorphisms and the susceptibility of HBV-related hepatocellular carcinoma in a Guangxi population.
Tumour Biol. 2016; 37(5):6599-606 [PubMed
] Related Publications
Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (PIN1) plays a critical role in different signaling pathways, cell cycle progression and proliferation, and gene expression, and it has been found to overexpress in many tumor tissues. Recently, researchers have found that PIN1 gene polymorphisms may alter the function of protein and be associated with the risk of cancer. The present study analyzed three common polymorphisms in promoter regions (rs2233678 and rs2233679) and in exon2 (rs2233682) of the PIN1 gene in 254 patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) and 235 healthy controls in a Guangxi study population to determine whether any relationship exists between the polymorphisms and the risk of HBV-related HCC. The results revealed that the rs2233679 TT genotype was associated with increased risk of HCC with HBV infection [odds ratio (OR) = 2.04, 95 % confidence interval (95 % CI) = 1.13-3.69, p = 0.019]. This association was stronger in men than in women (OR = 2.17, 95 % CI = 1.09-4.34, p = 0.028) as well as in men 50 years of age and older (OR = 3.91, 95 % CI = 1.29-11.80, p = 0.016); moreover, for alcohol drinkers, being a carrier of the PIN1 rs2233679 CT genotype had a moderately increased risk of HCC (OR = 3.98, 95 % CI = 1.02-15.57, p = 0.047). In contrast, people carrying the rs2233682 GA genotype and A alleles were 0.23 times more likely to develop HCC (OR = 0.23, 95 % CI = 0.06-0.87, p = 0.031 and OR = 0.23, 95 % CI = 0.06-0.87, p = 0.030). No such associations were found in the PIN1 rs2233678 polymorphisms between the HBV-related HCC cases and the controls. In addition, the haplotype GCA was found to be a high protection factor for HCC with HBV infection (OR = 0.14, 95 % CI = 0.03-0.62, p = 0.003). In conclusion, this study's findings suggest that the PIN1 rs2233679 TT genotype, the rs2233682GA genotype, and A alleles might be associated with the HBV-related HCC in a Guangxi study population.
Zhu Z, Zhang H, Lang F, et al.Pin1 promotes prostate cancer cell proliferation and migration through activation of Wnt/β-catenin signaling.
Clin Transl Oncol. 2016; 18(8):792-7 [PubMed
] Related Publications
BACKGROUND: Recent evidence suggests that the peptidyl-prolyl isomerase Pin1 is an oncoprotein that acts as a novel therapeutic target in a variety of tumors. In this study, we investigated the clinical significance of Pin1 and its function in prostate cancer (PCa) tumor progression.
METHODS: Immunohistochemical and quantitative RT-PCR analyses were performed to detect the expression of Pin1 in 86 PCa tissue samples. The functional role of Pin1 was evaluated by small interfering RNA-mediated depletion in PCa cells followed by analyses of cell proliferation and migration. Furthermore, the association between expression of Pin1 and levels of β-catenin and cyclin D1 was also evaluated.
RESULTS: Our results showed that the high expression of Pin1 staining was 66 of 86 (76.74 %) PCa samples, and in 25 of 86 (29.07 %) BPH tissues, the difference was statistically significant (P < 0.001). Pin1 was significantly elevated in all PCa cell lines when compared to the normal RWPE-1 cells. We observed that proliferation and migration of LNCaP cells were inhibited by Pin1 knockdown. The levels of β-catenin and cyclin D1 in clinical PCa specimens were positively associated with Pin1 expression.
CONCLUSIONS: Our results suggest that Pin1 plays an important role in tumorigenesis of PCa, suggesting that targeting Pin1 pathway could represent a potential modality for treating PCa.
BACKGROUND AND PURPOSE: Dipeptidyl peptidase 4 (DPP4) is an aminopeptidase that is widely expressed in different cell types. Recent studies suggested that DPP4 plays an important role in tumour progression in several human malignancies. Here we have examined the mechanisms by which up-regulation of DPP4 expression causes epithelial transformation and mammary tumourigenesis.
EXPERIMENTAL APPROACH: Expression of DPP4 and the peptidylprolyl cis/trans isomerase, NIMA-interacting 1 (PIN1), and the cytotoxic effects of combined treatment with sitagliptin and juglone were investigated by immunohistochemistry, immunoblotting, real-time PCR, TUNEL and soft agar assays, using MCF7 cells. The effects of sitagliptin on tumour development in vivo were studied in the syngeneic 4T1 metastatic breast cancer model.
KEY RESULTS: Activity of the transcription factor E2F1 induced by EGF was enhanced by DPP4, thus increasing PIN1 expression. Furthermore, DPP4 enhanced MEK/ERK and JNK/c-Jun signalling induced by EGF, inducing AP-1 activity and epithelial cell transformation. In contrast, DPP4 silencing or DPP4 inhibition in MCF7 cells inhibited PIN1 expression via E2F1 activity induced by EGF, decreasing colony formation and inducing DNA fragmentation. In the syngeneic 4T1 metastatic breast cancer model, DPP4 overexpression increased tumour development, whereas treatment with sitagliptin and/or juglone suppressed it. Consistent with these observations, DPP4 levels were positively correlated with PIN1 expression in human breast cancer.
CONCLUSIONS AND IMPLICATIONS: DPP4 promoted EGF-induced epithelial cell transformation and mammary tumourigenesis via induction of PIN1 expression, suggesting that sitagliptin targeting of DPP4 could be a treatment strategy in patients with breast cancer.
Hu YG, Shen YF, Li YEffect of Pin1 inhibitor juglone on proliferation, migration and angiogenic ability of breast cancer cell line MCF7Adr.
J Huazhong Univ Sci Technolog Med Sci. 2015; 35(4):531-4 [PubMed
] Related Publications
This study aimed to evaluate the effects of Pin1 inhibitor Juglone on proliferation, migration and the angiogenic ability of breast cancer cell line MCF7Adr. MCF7Adr cells were cultured and separately treated with Pin1 inhibitor Juglone (treatment group) and DMEM without drug (control group). The cell cycle was examined by flow cytometry. Cell migration was measured by wound-healing assay. Cyclin E protein content was detected by Western blotting. The angiogenesis factor vascular endothelial growth factor (VEGF) in cell media was determined by enzyme linked immunosorbent assay. The results showed that the percentage of cells in G2/M phase in treatment group was significantly higher than that in control group (25.5% vs. 10.1%, P<0.05), and that in G0/G1 phase and S stage in treatment group was significantly lower than that in control group (40.5% vs. 48.2%, and 33.7% vs. 41.7%, P<0.05). Cyclin E protein content in treatment group was significantly lower than that in control group (39.2 ± 7.4 vs. 100 ± 23.1, P<0.05). (A0-A24)/A0 value in treatment group was significantly lower than that in control group (23.9 ± 3.8 vs. 100 ± 14.4, P<0.05). VEGF-A, -B, and -C contents in cell media of treatment group were significantly lower than those in control group (P<0.05). It was suggested that Pin1 inhibitor Juglone can effectively inhibit the proliferation, migration and the angiogenic ability of MCF7Adr cells, and can be used as an alternative drug therapy for breast cancer.
Kanaoka R, Kushiyama A, Seno Y, et al.Pin1 Inhibitor Juglone Exerts Anti-Oncogenic Effects on LNCaP and DU145 Cells despite the Patterns of Gene Regulation by Pin1 Differing between These Cell Lines.
PLoS One. 2015; 10(6):e0127467 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Prostate cancer initially develops in an androgen-dependent manner but, during its progression, transitions to being androgen-independent in the advanced stage. Pin1, one of the peptidyl-prolyl cis/trans isomerases, is reportedly overexpressed in prostate cancers and is considered to contribute to accelerated cell growth, which may be one of the major factors contributing to their androgen-independent growth. Thus, we investigated how Pin1 modulates the gene expressions in both androgen-dependent and androgen-independent prostate cancer cell lines using microarray analysis. In addition, the effects of Juglone, a commercially available Pin1 inhibitor were also examined.
METHODS: Two prostate cancer cell-lines, LNCaP (androgen-dependent) and DU145 (androgen-independent), were treated with Pin1 siRNA and its effects on gene expressions were analyzed by microarray. Individual gene regulations induced by Pin1 siRNA or the Pin1 inhibitor Juglone were examined using RT-PCR. In addition, the effects of Juglone on the growth of LNCaP and DU145 transplanted into mice were investigated.
RESULTS: Microarray analysis revealed that transcriptional factors regulated by Pin1 differed markedly between LNCaP and DU145 cells, the only exception being that Nrf was regulated in the same way by Pin1 siRNA in both cell lines. Despite this marked difference in gene regulations, Pin1 siRNA and Juglone exert a strong inhibitory effect on both the LNCaP and the DU145 cell line, suppressing in vitro cell proliferation as well as tumor enlargement when transplanted into mice.
CONCLUSIONS: Despite Pin1-regulated gene expressions differing between these two prostate cancer cell-lines, LNCaP (androgen-dependent) and DU145 (androgen-independent), Pin1 inhibition suppresses proliferation of both cell-lines. These findings suggest the potential effectiveness of Pin1 inhibitors as therapeutic agents for prostate cancers, regardless of their androgen sensitivity.
Kaklamani VG, Jeruss JS, Hughes E, et al.Phase II neoadjuvant clinical trial of carboplatin and eribulin in women with triple negative early-stage breast cancer (NCT01372579).
Breast Cancer Res Treat. 2015; 151(3):629-38 [PubMed
] Related Publications
The purpose of this study is to evaluate the efficacy and safety of neoadjuvant treatment with carboplatin and eribulin in patients with early-stage triple negative breast cancer (TNBC), and to explore biomarkers based on DNA and protein expression profiles as predictors of response. Patients with histologically confirmed early-stage TNBC received carboplatin AUC 6 iv every 21 days, and eribulin 1.4 mg/m(2) day 1 and day 8 every 21 days for four cycles. The primary endpoint of the study was pathologic complete response (pCR), with secondary endpoints including clinical response and safety of the combination. Exploratory studies assessed DNA-based biomarkers [homologous recombination deficiency (HRD) score, and HR deficiency status (HRD score + BRCA1/BRCA2 mutation status)], protein-based biomarkers (Ki67, TP53, androgen receptor, Cyclin E, CDK2, Cyclin D, CDK4, Pin1 and Smad3), and clinical pretreatment factors as predictors of pCR. 13/30 (43.3 %) patients enrolled in the study achieved pCR. 24 (80.0 %) had a clinical complete or partial response. The combination was safe with mostly grade 1 and 2 toxicities. HRD score (P = 0.0024) and HR deficiency status (P = 0.0012) significantly predicted pCR. Pretreatment cytoplasmic CDK2 was also associated with pCR (P = 0.021). Significant differences in pre- versus post-treatment expression levels of nuclear Cyclin D (P = 0.020), nuclear CDK4 (P = 0.0030), and nuclear Smad3 (P = 0.015) were detected. The combination of carboplatin and eribulin is safe and efficacious in the treatment of early-stage TNBC. HRD score, HR deficiency status, and cytoplasmic CDK2 predicted pCR in this patient population.
Su YH, Tang WC, Cheng YW, et al.Targeting of multiple oncogenic signaling pathways by Hsp90 inhibitor alone or in combination with berberine for treatment of colorectal cancer.
Biochim Biophys Acta. 2015; 1853(10 Pt A):2261-72 [PubMed
] Related Publications
There is a wide range of drugs and combinations under investigation and/or approved over the last decade to treat colorectal cancer (CRC), but the 5-year survival rate remains poor at stages II-IV. Therefore, new, more-efficient drugs still need to be developed that will hopefully be included in first-line therapy or overcome resistance when it appears, as part of second- or third-line treatments in the near future. In this study, we revealed that heat shock protein 90 (Hsp90) inhibitors have high therapeutic potential in CRC according to combinative analysis of NCBI's Gene Expression Omnibus (GEO) repository and chemical genomic database of Connectivity Map (CMap). We found that second generation Hsp90 inhibitor, NVP-AUY922, significantly downregulated the activities of a broad spectrum of kinases involved in regulating cell growth arrest and death of NVP-AUY922-sensitive CRC cells. To overcome NVP-AUY922-induced upregulation of survivin expression which causes drug insensitivity, we found that combining berberine (BBR), a herbal medicine with potency in inhibiting survivin expression, with NVP-AUY922 resulted in synergistic antiproliferative effects for NVP-AUY922-sensitive and -insensitive CRC cells. Furthermore, we demonstrated that treatment of NVP-AUY922-insensitive CRC cells with the combination of NVP-AUY922 and BBR caused cell growth arrest through inhibiting CDK4 expression and induction of microRNA-296-5p (miR-296-5p)-mediated suppression of Pin1-β-catenin-cyclin D1 signaling pathway. Finally, we found that the expression level of Hsp90 in tumor tissues of CRC was positively correlated with CDK4 and Pin1 expression levels. Taken together, these results indicate that combination of NVP-AUY922 and BBR therapy can inhibit multiple oncogenic signaling pathways of CRC.
The transcriptional activity of estrogen receptor α (ERα), the key driver of breast cancer proliferation, is enhanced by multiple cellular interactions, including phosphorylation-dependent interaction with Pin1, a proline isomerase, which mediates cis-trans isomerization of the N-terminal Ser(P)(118)-Pro(119) in the intrinsically disordered AF1 (activation function 1) domain of ERα. Because both ERα and Pin1 have multiple cellular partners, it is unclear how Pin1 assists in the regulation of ERα transactivation mechanisms and whether the functional effects of Pin1 on ERα signaling are direct or indirect. Here, we tested the specific action of Pin1 on an essential step in ERα transactivation, binding to specific DNA sites. DNA binding analysis demonstrates that stable overexpression of Pin1 increases endogenous ERα DNA binding activity when activated by estrogen but not by tamoxifen or EGF. Increased DNA binding affinity is a direct effect of Pin1 on ERα because it is observed in solution-based assays with purified components. Further, our data indicate that isomerization is required for Pin1-modulation of ERα-DNA interactions. In an unbiased in vitro DNA binding microarray with hundreds of thousands of permutations of ERα-binding elements, Pin1 selectively enhances the binding affinity of ERα to consensus DNA elements. These studies reveal that Pin1 isomerization of phosphorylated ERα can directly regulate the function of the adjacent DNA binding domain, and this interaction is further modulated by ligand binding in the ligand-binding domain, providing evidence for Pin1-dependent allosteric regulation of ERα function.
A common key regulator of oncogenic signaling pathways in multiple tumor types is the unique isomerase Pin1. However, available Pin1 inhibitors lack the required specificity and potency for inhibiting Pin1 function in vivo. By using mechanism-based screening, here we find that all-trans retinoic acid (ATRA)--a therapy for acute promyelocytic leukemia (APL) that is considered the first example of targeted therapy in cancer, but whose drug target remains elusive--inhibits and degrades active Pin1 selectively in cancer cells by directly binding to the substrate phosphate- and proline-binding pockets in the Pin1 active site. ATRA-induced Pin1 ablation degrades the protein encoded by the fusion oncogene PML-RARA and treats APL in APL cell and animal models as well as in human patients. ATRA-induced Pin1 ablation also potently inhibits triple-negative breast cancer cell growth in human cells and in animal models by acting on many Pin1 substrate oncogenes and tumor suppressors. Thus, ATRA simultaneously blocks multiple Pin1-regulated cancer-driving pathways, an attractive property for treating aggressive and drug-resistant tumors.
Proline-directed phosphorylation is regulated by the prolyl isomerase Pin1, which plays a fundamental role in driving breast cancer stem-like cells (BCSCs). Rab2A is a small GTPase critical for vesicle trafficking. Here, we show that Pin1 increases Rab2A transcription to promote BCSC expansion and tumorigenesis in vitro and in vivo. Mechanistically, Rab2A directly interacts with and prevents dephosphorylation/inactivation of Erk1/2 by the MKP3 phosphatase, resulting in Zeb1 upregulation and β-catenin nuclear translocation. In cancer cells, Rab2A is activated via gene amplification, mutation or Pin1 overexpression. Rab2A overexpression or mutation endows BCSC traits to primary normal human breast epithelial cells, whereas silencing Rab2A potently inhibits the expansion and tumorigenesis of freshly isolated BCSCs. Finally, Rab2A overexpression correlates with poor clinical outcome in breast cancer patients. Thus, Pin1/Rab2A/Erk drives BCSC expansion and tumorigenicity, suggesting potential drug targets.
BACKGROUND: Histone deacetylase 3 (HDAC3) is overexpressed in cancers and its inhibition enhances anti-tumor chemotherapy. ZBP-89, a transcription factor, can induce pro-apoptotic Bak and reduce HDAC3 but the mechanism is unknown. Pin1, a molecular switch that determines the fate of phosphoproteins, is known to interact with HDAC3. The aim of this study was to investigate the mechanism how ZBP-89 downregulated HDAC3.
METHODS: In this study, liver cells, Pin1-knockout Pin1(-/-) and Pin1 wild-typed Pin(+/+) cells were used to explore how ZBP-89 reduced HDAC3. The overexpression of ZBP-89 was achieved by infecting cells with Ad-ZBP-89, an adenoviral construct containing ZBP-89 gene. The role of NF-κB was determined using CAY10576, MG132 and SN50, the former two being inhibitors of IκB degradation and SN50 being an inhibitor of p65/p50 translocation. A xenograft tumor model was used to confirm the in vitro data.
RESULTS: ZBP-89 reduced HDAC3, and it could form a complex with IκB and induce IκB phosphorylation to inhibit IκB. Furthermore, ZBP-89-mediated HDAC3 reduction was suppressed by IκB degradation inhibitors CAY10576 and MG132 but not by p65/p50 translocation inhibitor SN50, indicating that IκB decrease rather than the elevated activity of NF-κB contributed to HDAC3 reduction. ZBP-89-mediated HDAC3 or IκB reduction was significantly less obvious in Pin1(-/-) cells compared with Pin1(+/+) cells. In Ad-ZBP-89-infected Pin1(+/+) cancer cells, Pin1 siRNA increased HDAC3 but decreased Bak, compared with cells without ZBP-89 infection. These findings indicate that Pin1 participates in ZBP-89-mediated HDAC3 downregulation and Bak upregulation. The cell culture result was confirmed by in vivo mouse tumor model experiments.
CONCLUSIONS: ZBP-89 attenuates HDAC3 by increasing IκB degradation. Such attenuation is independent of NF-κB activity but partially depends on Pin1. The novel pathway identified may help generate new anti-cancer strategy by targeting HDAC3 and its related molecules.
Yao J, Wang JM, Wang ZL, Wu YNThe Pin1 gene polymorphism and the susceptibility of oral squamous cell carcinoma in East China.
Cancer Biomark. 2014; 14(6):441-7 [PubMed
] Related Publications
Pin1 is a peptidylprolyl isomerase that specifically recognizes phosphorylated Pro-directed Ser/Thr (pSer/Thr-Pro) peptide sequences. Genetic variants in the Pin1 gene may alter protein function and cancer risk. In this study, we genotyped the two common promoter polymorphisms -842G/C (rs2233678) and -667T/C (rs2233679) in two independent hospital-based case-control studies conducted in Eastern Chinese populations, including 209 patients with oral squamous cell carcinoma and 444 cancer-free controls. We found -667TT heterozygotes had a significantly increased risk of oral squamous cell carcinoma (P=0.028, OR=1.66, 95%CI=1.02-2.69). However, there was no risk significant associated with the -842G/C polymorphism. Further large population-based studies are needed to confirm these results.
Lin YC, Lu LT, Chen HY, et al.SCP phosphatases suppress renal cell carcinoma by stabilizing PML and inhibiting mTOR/HIF signaling.
Cancer Res. 2014; 74(23):6935-46 [PubMed
] Related Publications
The tumor-suppressor protein promyelocytic leukemia (PML) is aberrantly degraded in multiple types of human cancers through mechanisms that are incompletely understood. Here, we show that the phosphatase SCP1 and its isoforms SCP2/3 dephosphorylate PML at S518, thereby blocking PML ubiquitination and degradation mediated by the prolyl isomerase Pin1 and the ubiquitin ligase KLHL20. Clinically, SCP1 and SCP3 are downregulated in clear cell renal cell carcinoma (ccRCC) and these events correlated with PMLS518 phosphorylation, PML turnover, and high-grade tumors. Restoring SCP1-mediated PML stabilization not only inhibited malignant features of ccRCC, including proliferation, migration, invasion, tumor growth, and tumor angiogenesis, but also suppressed the mTOR-HIF pathway. Furthermore, blocking PML degradation in ccRCC by SCP1 overexpression or Pin1 inhibition enhanced the tumor-suppressive effects of the mTOR inhibitor temsirolimus. Taken together, our results define a novel pathway of PML degradation in ccRCC that involves SCP downregulation, revealing contributions of this pathway to ccRCC progression and offering a mechanistic rationale for combination therapies that jointly target PML degradation and mTOR inhibition for ccRCC treatment.
BACKGROUND: Pin1 promotes oncogenesis by regulating multiple oncogenic signaling. In this study, we investigated the involvement of Pin1 in tumor progression and in the prognosis of human esophageal squamous cell carcinoma (ESCC).
RESULTS: We observed that proliferation, clonogenicity and tumorigenesis of CE81T cells were inhibited by Pin1 knockdown. We next analyzed Pin1 expression in clinical ESCC specimens. When compared to the corresponding non-tumor part, Pin1 protein and mRNA levels in tumor part were higher in 84% and 62% patients, respectively. By immunohistochemistry, we identified that high Pin1 expression was associated with higher primary tumor stage (p = 0.035), higher overall cancer stage (p = 0.047) and poor overall survival (p < 0.001). Furthermore, the association between expression of Pin1 and levels of β-catenin and cyclin D in cell line and clinical specimens was evaluated. β-catenin and cyclin D1 were decreased in CE81T cells with Pin1 knockdown. Cyclin D1 level correlated with Pin1 expression in clinical ESCC specimens.
CONCLUSIONS: Pin1 upregulation was associated with advanced stage and poor prognosis of ESCC. Pin1 knockdown inhibited aggressiveness of ESCC cells. β-catenin and cyclin D1 were positively regulated by Pin1. These results indicated that targeting Pin1 pathway could represent a potential modality for treating ESCC.
Sorrentino G, Comel A, Mantovani F, Del Sal GRegulation of mitochondrial apoptosis by Pin1 in cancer and neurodegeneration.
Mitochondrion. 2014; 19 Pt A:88-96 [PubMed
] Related Publications
Mitochondria are sensitive and efficient organelles that regulate essential biological processes including: energy metabolism, decoding and transduction of intracellular signals, and balance between cell death and survival. Of note, dysfunctions in mitochondrial physiology are a general hallmark of cancer cells, leading to transformation-related features such as altered cellular metabolism, survival under stress conditions and reduced apoptotic response to chemotherapy. Mitochondrial apoptosis is a finely regulated process that derives from activation of multiple signaling networks. A crucial biochemical requirement for transducing pro-apoptotic stimuli is represented by kinase-dependent phosphorylation cascades. In this context a pivotal role is played by the prolyl-isomerase Pin1, which translates Ser/Thr-Pro phosphorylation into conformational changes able to modify the activities of its substrates. In this review we will discuss the impact of Pin1 in regulating various aspects of apoptosis in different biological contexts with particular emphasis on cancer and neurodegenerative diseases.
Driver JAInverse association between cancer and neurodegenerative disease: review of the epidemiologic and biological evidence.
Biogerontology. 2014; 15(6):547-57 [PubMed
] Related Publications
Growing evidence suggests an unusual epidemiologic association between cancer and certain neurological conditions, particularly age-related neurodegenerative diseases. Cancer survivors have a 20-50% lower risk of developing Parkinson's and Alzheimer's disease, and patients with these neurodegenerative conditions have a substantially lower incidence of cancer. We review the epidemiologic evidence for this inverse co-morbidity and show that it is not simply an artifact of survival bias or under-diagnosis. We then review the potential biological explanations for this association, which is intimately linked to the very different nature of dividing cells and neurons. The known genetic and metabolic connections between cancer and neurodegeneration generally fall within two categories. The first includes shared genes and pathways such as Pin1 and the ubiquitin proteasome system that are dysregulated in different directions to cause one disease or the other. The second includes common pathophysiological mechanisms such as mitochondrial dysfunction, oxidative stress and DNA damage that drive both conditions, but with different cellular fates. We discuss examples of these biological links and their implications for developing new approaches to prevention and treatment of both diseases.
Lee KH, Lin FC, Hsu TI, et al.MicroRNA-296-5p (miR-296-5p) functions as a tumor suppressor in prostate cancer by directly targeting Pin1.
Biochim Biophys Acta. 2014; 1843(9):2055-66 [PubMed
] Related Publications
Upregulation of Pin1 was shown to advance the functioning of several oncogenic pathways. It was recently shown that Pin1 is potentially an excellent prognostic marker and can also serve as a novel therapeutic target for prostate cancer. However, the molecular mechanism of Pin1 overexpression in prostate cancer is still unclear. In the present study, we showed that the mRNA expression levels of Pin1 were not correlated with Pin1 protein levels in prostate cell lines which indicated that Pin1 may be regulated at the post-transcriptional level. A key player in post-transcriptional regulation is represented by microRNAs (miRNAs) that negatively regulate expressions of protein-coding genes at the post-transcriptional level. A bioinformatics analysis revealed that miR-296-5p has a conserved binding site in the Pin1 3'-untranslated region (UTR). A luciferase reporter assay demonstrated that the seed region of miR-296-5p directly interacts with the 3'-UTR of Pin1 mRNA. Moreover, miR-296-5p expression was found to be inversely correlated with Pin1 expression in prostate cancer cell lines and prostate cancer tissues. Furthermore, restoration of miR-296-5p or the knockdown of Pin1 had the same effect on the inhibition of the ability of cell proliferation and anchorage-independent growth of prostate cancer cell lines. Our results support miR-296-5p playing a tumor-suppressive role by targeting Pin1 and implicate potential effects of miR-296-5p on the prognosis and clinical application to prostate cancer therapy.
FBW7 (F-box and WD repeat domain-containing 7) or Fbxw7 is a tumor suppressor, which promotes the ubiquitination and subsequent degradation of numerous oncoproteins including Mcl-1, Cyclin E, Notch, c- Jun, and c-Myc. In turn, FBW7 is regulated by multiple upstream factors including p53, C/EBP-δ, EBP2, Pin1, Hes-5 and Numb4 as well as by microRNAs such as miR-223, miR-27a, miR-25, and miR-129-5p. Given that the Fbw7 tumor suppressor is frequently inactivated or deleted in various human cancers, targeting FBW7 regulators is a promising anti-cancer therapeutic strategy.
Yun HJ, Kim JY, Kim G, Choi HSProlyl-isomerase Pin1 impairs trastuzumab sensitivity by up-regulating fatty acid synthase expression.
Anticancer Res. 2014; 34(3):1409-16 [PubMed
] Related Publications
BACKGROUND/AIM: Clinical trials have shown efficacy of the anti-HER2 monoclonal antibody trastuzumab in metastatic breast cancer patients. The aim of the present study was to elucidate the mechanisms by which up-regulation of fatty acid synthase (FAS) expression confers resistance to trastuzumab in HER2-positive breast cancers.
MATERIALS AND METHODS: The expression of FAS as well as the cytotoxic effects of combinatorial treatment of trastuzumab and juglone was investigated by immunoblotting, BrdU incorporation, TUNEL assay, and soft agar assay.
RESULTS: Pin1 enhanced EGF-induced SREBP1c promoter activity, resulting in the induction of FAS expression in BT474 cells. In contrast, juglone, a potent Pin1 inhibitor, significantly enhanced trastuzumab-induced FAS down-regulation and cell death in BT474 cells. Furthermore, trastuzumab, when used in combination with gene silencing or chemical inhibition of Pin1, increased cleaved poly(ADP-ribose) polymerase and DNA fragmentation to increase trastuzumab sensitivity.
CONCLUSION: Pin1-mediated FAS overexpression is a major regulator of trastuzumab-resistant breast cancer growth and survival.
Ibáñez K, Boullosa C, Tabarés-Seisdedos R, et al.Molecular evidence for the inverse comorbidity between central nervous system disorders and cancers detected by transcriptomic meta-analyses.
PLoS Genet. 2014; 10(2):e1004173 [PubMed
] Free Access to Full Article Related Publications
There is epidemiological evidence that patients with certain Central Nervous System (CNS) disorders have a lower than expected probability of developing some types of Cancer. We tested here the hypothesis that this inverse comorbidity is driven by molecular processes common to CNS disorders and Cancers, and that are deregulated in opposite directions. We conducted transcriptomic meta-analyses of three CNS disorders (Alzheimer's disease, Parkinson's disease and Schizophrenia) and three Cancer types (Lung, Prostate, Colorectal) previously described with inverse comorbidities. A significant overlap was observed between the genes upregulated in CNS disorders and downregulated in Cancers, as well as between the genes downregulated in CNS disorders and upregulated in Cancers. We also observed expression deregulations in opposite directions at the level of pathways. Our analysis points to specific genes and pathways, the upregulation of which could increase the incidence of CNS disorders and simultaneously lower the risk of developing Cancer, while the downregulation of another set of genes and pathways could contribute to a decrease in the incidence of CNS disorders while increasing the Cancer risk. These results reinforce the previously proposed involvement of the PIN1 gene, Wnt and P53 pathways, and reveal potential new candidates, in particular related with protein degradation processes.
Cancer treatments induce cell stress to trigger apoptosis in tumor cells. Many cancers repress these apoptotic signals through alterations in the Bcl2 proteins that regulate this process. Therapeutics that target these specific survival biases are in development, and drugs that inhibit Bcl2 activities have shown clinical activity for some cancers. Mcl1 is a survival factor for which no effective antagonists have been developed, so it remains a principal mediator of therapy resistance, including to Bcl2 inhibitors. We used a synthetic-lethal screening strategy to identify genes that regulate Mcl1 survival activity using the pediatric tumor neuroblastoma (NB) as a model, as a large subset are functionally verified to be Mcl1 dependent and Bcl2 inhibitor resistant. A targeted siRNA screen identified genes whose knockdown restores sensitivity of Mcl1-dependent NBs to ABT-737, a small molecule inhibitor of Bcl2, BclXL and BclW. Three target genes that shifted the ABT-737 IC50 >1 log were identified and validated: PSMD14, UBL5 and PRPF8. The latter two are members of a recently characterized subcomplex of the spliceosome that along with SART1 is responsible for non-canonical 5'-splice sequence recognition in yeast. We showed that SART1 knockdown similarly sensitized Mcl1-dependent NB to ABT-737 and that triple knockdown of UBL5/PRPF8/SART1 phenocopied direct MCL1 knockdown, whereas having no effect on Bcl2-dependent NBs. Both genetic spliceosome knockdown or treatment with SF3b-interacting spliceosome inhibitors like spliceostatin A led to preferential pro-apoptotic Mcl1-S splicing and reduced translation and abundance of Mcl1 protein. In contrast, BN82865, which inhibits the second transesterification step in terminal spliceosome processing, did not have this effect. These findings demonstrate a prominent role for the spliceosome in mediating Mcl1 activity and suggest that drugs that target either the specific UBL5/PRPF8/SART1 subcomplex or SF3b functions may have a role as cancer therapeutics by attenuating the Mcl1 survival bias present in numerous cancers.
Kim K, Kim G, Kim JY, et al.Interleukin-22 promotes epithelial cell transformation and breast tumorigenesis via MAP3K8 activation.
Carcinogenesis. 2014; 35(6):1352-61 [PubMed
] Related Publications
Interleukin-22 (IL-22), one of the cytokines secreted by T-helper 17 (Th17) cells, binds to a class II cytokine receptor containing an IL-22 receptor 1 (IL-22R1) and IL-10R2 and influences a variety of immune reactions. IL-22 has also been shown to modulate cell cycle and proliferation mediators such as extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), but little is known about the underlying molecular mechanisms of IL-22 in tumorigenesis. In this paper, we propose that IL-22 has a crucial role to play in controlling epithelial cell proliferation and tumorigenesis in the breast. IL-22 increased MAP3K8 phosphorylation through IL-22R1, followed by the induction of MEK-ERK, JNK-c-Jun, and STAT3 signaling pathways. Furthermore, IL-22-IL-22R1 signaling pathway activated activator protein-1 and HER2 promoter activity. In addition, Pin1 was identified as a key positive regulator for the phosphorylation-dependent MEK, c-Jun and STAT3 activity induced by IL-22. Pin1(-/-) mouse embryonic fibroblasts (MEF) exhibited significantly a decrease in IL-22-induced MEK1/2, c-Jun, and STAT3 phosphorylation compared with Pin1(+/+) MEF. In addition, a knockdown of Pin1 prevented phosphorylation induced by IL-22. The in vivo chorioallantoic membrane assay also showed that IL-22 increased tumor formation of JB6 Cl41 cells. Moreover, the knockdown of MAP3K8 and Pin1 attenuated tumorigenicity of MCF7 cells. Consistent with these observations, IL-22 levels positively correlate with MAP3K8 and Pin1 expression in human breast cancer. Overall, our findings point to a critical role for the IL-22-induced MAP3K8 signaling pathway in promoting cancer-associated inflammation in the tumor microenvironment.