The PIM1 kinase is a critical component of a survival pathway activated by docetaxel and promotes survival of docetaxel-treated prostate cancer cells.
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ABSTRACT:
SUBMITTER: Zemskova M
PROVIDER: S-EPMC3258959 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Metastatic prostate cancer is presently incurable. The oncogenic protein PTOV1, first described in prostate cancer, was reported as overexpressed and significantly correlated with poor survival in numerous tumors. Here, we investigated the role of PTOV1 in prostate cancer survival to docetaxel and self-renewal ability. Transduction of PTOV1 in docetaxel-sensitive Du145 and PC3 cells significantly increased cell survival after docetaxel exposure and induced docetaxel-resistance genes expression (ABCB1, CCNG2 and TUBB2B). In addition, PTOV1 induced prostatospheres formation and self-renewal genes expression (ALDH1A1, LIN28A, MYC and NANOG). In contrast, Du145 and PC3 cells knockdown for PTOV1 significantly accumulated in the G2/M phase, presented a concomitant increased subG1 peak, and cell death by apoptosis. These effects were enhanced in docetaxel-resistant cells. Analyses of tumor datasets show that PTOV1 expression significantly correlated with prostate tumor grade, drug resistance (CCNG2) and self-renewal (ALDH1A1, MYC) markers. These genes are concurrently overexpressed in most metastatic lesions. Metastases also show PTOV1 genomic amplification in significant co-occurrence with docetaxel-resistance and self-renewal genes. Our findings identify PTOV1 as a promoter of docetaxel-resistance and self-renewal characteristics for castration resistant prostate cancer. The concomitant increased expression of PTOV1, ALDH1A1 and CCNG2 in primary tumors, may predict metastasis and bad prognosis.
| S-EPMC5601723 | biostudies-literature
Project description:There are few data regarding disparities in overall survival (OS) between Asian and white men with metastatic castration-resistant prostate cancer (mCRPC). We compared OS of Asian and white mCRPC men treated in phase III clinical trials with docetaxel and prednisone (DP) or a DP-containing regimen. Individual participant data from 8820 men with mCRPC randomly assigned on nine phase III trials to receive DP or a DP-containing regimen were combined. Men enrolled in these trials had a diagnosis of prostate adenocarcinoma. The median overall survival was 18.8?months (95% confidence interval [CI] = 17.4 to 22.1 months) and 21.2?months (95% CI?=?20.8 to 21.7 months) for Asian and white men, respectively. The pooled hazard ratio for death for Asian men compared with white men, adjusted for baseline prognostic factors, was 0.95 (95% CI?=?0.84 to 1.09), indicating that Asian men were not at increased risk of death. This large analysis showed that Asian men did not have shorter OS duration than white men treated with docetaxel.
| S-EPMC7190204 | biostudies-literature
Project description:BackgroundPre-treatment androgen levels are associated with overall survival (OS) in patients with metastatic castration-resistant prostate cancer (CRPC) treated with androgen synthesis inhibitors. The current study sought to determine whether pre-treatment serum androgens predict clinical outcome among patients with metastatic CRPC treated with docetaxel chemotherapy.Materials and methodsData were obtained from 1050 men who were chemotherapy-naive prior to treatment with docetaxel, prednisone, and either bevacizumab or placebo (CALGB 90401). Pretreatment serum assays for testosterone, androstenedione, and dehydroepiandrosterone (DHEA) were performed with tandem liquid chromatography-mass spectrometry.ResultsMedian values for testosterone, androstenedione, and DHEA were 1.00, 13.50, and 8.12 ng/dL, respectively. The median was used to define the midpoint between low and high values. In univariate analysis, median OS for low versus high levels was 21.4 and 24.2 months for testosterone, 23.8 and 21.9 months for androstenedione, and 20.2 and 25.2 months for DHEA (P = NS). In multivariable analysis of all androgens, baseline DHEA was prognostic of ≥ 50% PSA decline from baseline (P = .008). In multivariable analysis adjusting for 10 known prognostic values and prior ketoconazole use for metastatic CRPC, a 10-unit increase in baseline testosterone increased risk of death (hazard ratio, 1.11; 95% confidence interval, 1.01-1.23; P = .039), whereas a 10-unit increase in androstenedione lowered risk of death (hazard ratio, 0.92; 95% confidence interval, 0.88-0.97; P = .001).ConclusionConsistent with prior studies, higher androstenedione levels in patients with metastatic CRPC treated with docetaxel are associated with improved survival. However pretreatment levels of other androgen levels are associated with varied effects on clinical outcome in chemotherapy-treated patients.
| S-EPMC7252587 | biostudies-literature
Project description:Prostate cancer (PCa) is the second leading cause of cancer death in the US. Death from PCa primarily results from metastasis. Mitogen-activated protein kinase kinase 4 (MAP2K4) is overexpressed in invasive PCa lesions in humans, and can be inhibited by small molecule therapeutics that demonstrate favorable activity in phase II studies. However, MAP2K4's role in regulating metastatic behavior is controversial and unknown. To investigate, we engineered human PCa cell lines which overexpress either wild type or constitutive active MAP2K4. Orthotopic implantation into mice demonstrated MAP2K4 increases formation of distant metastasis. Constitutive active MAP2K4, though not wild type, increases tumor size and circulating tumor cells in the blood and bone marrow. Complementary in vitro studies establish stable MAP2K4 overexpression promotes cell invasion, but does not affect cell growth or migration. MAP2K4 overexpression increases the expression of heat shock protein 27 (HSP27) protein and protease production, with the largest effect upon matrix metalloproteinase 2 (MMP-2), both in vitro and in mouse tumor samples. Further, MAP2K4-mediated increases in cell invasion are dependent upon heat shock protein 27 (HSP27) and MMP-2, but not upon MAP2K4's immediate downstream targets, p38 MAPK or JNK. We demonstrate that MAP2K4 increases human PCa metastasis, and prolonged over expression induces long term changes in cell signaling pathways leading to independence from p38 MAPK and JNK. These findings provide a mechanistic explanation for human studies linking increases in HSP27 and MMP-2 to progression to metastatic disease. MAP2K4 is validated as an important therapeutic target for inhibiting human PCa metastasis.
| S-EPMC4096757 | biostudies-literature
Project description:The PIM1 oncogene is over-expressed in human prostate cancer epithelial cells. Importantly, we observe that in human hyperplastic and cancerous prostate glands PIM1 is also markedly elevated in prostate fibroblasts, suggesting an important role for this kinase in epithelial/stromal crosstalk. The ability of PIM1 to regulate the biologic activity of stromal cells is demonstrated by the observation that expression of PIM1 kinase in human prostate fibroblasts increases the level and secretion of the extracellular matrix molecule, collagen 1A1 (COL1A1), the pro-inflammatory chemokine CCL5, and the platelet-derived growth factor receptors (PDGFR). PIM1 is found to regulate the transcription of CCL5. In co-cultivation assays where PIM1 over-expressing fibroblasts are grown with BPH1 prostate epithelial cells, PIM1 activity markedly enhances the ability of these fibroblasts to differentiate into myofibroblasts and express known markers of cancer-associated fibroblasts (CAFs). This differentiation can be reversed by the addition of small molecule PIM kinase inhibitors. Western blots demonstrate that PIM1 expression in prostate fibroblasts stimulates the phosphorylation of molecules that regulate 5'Cap driven protein translation, including 4EBP1 and eIF4B. Consistent with the hypothesis that the kinase controls translation of specific mRNAs in prostate fibroblasts, we demonstrate that PIM1 expression markedly increases the level of COL1A1 and PDGFR? mRNA bound to polysomes. Together these results point on PIM1 as a novel factor in regulation of the phenotype and differentiation of fibroblasts in prostate cancer by controlling both the transcription and translation of specific mRNAs.
| S-EPMC4314374 | biostudies-literature
Project description:PURPOSE:Several studies have reported that among patients with localized prostate cancer, black men have a shorter overall survival (OS) time than white men, but few data exist for men with advanced prostate cancer. The primary goal of this analysis was to compare the OS in black and white men with metastatic castration-resistant prostate cancer (mCRPC) who were treated in phase III clinical trials with docetaxel plus prednisone (DP) or a DP-containing regimen. METHODS:Individual participant data from 8,820 men with mCRPC randomly assigned in nine phase III trials to DP or a DP-containing regimen were combined. Race was based on self-report. The primary end point was OS. The Cox proportional hazards regression model was used to assess the prognostic importance of race (black v white) adjusted for established risk factors common across the trials (age, prostate-specific antigen, performance status, alkaline phosphatase, hemoglobin, and sites of metastases). RESULTS:Of 8,820 men, 7,528 (85%) were white, 500 (6%) were black, 424 (5%) were Asian, and 368 (4%) were of unknown race. Black men were younger and had worse performance status, higher testosterone and prostate-specific antigen, and lower hemoglobin than white men. Despite these differences, the median OS was 21.0 months (95% CI, 19.4 to 22.5 months) versus 21.2 months (95% CI, 20.8 to 21.7 months) in black and white men, respectively. The pooled multivariable hazard ratio of 0.81 (95% CI, 0.72 to 0.91) demonstrates that overall, black men have a statistically significant decreased risk of death compared with white men ( P < .001). CONCLUSION:When adjusted for known prognostic factors, we observed a statistically significant increased OS in black versus white men with mCRPC who were enrolled in these clinical trials. The mechanism for these differences is not known.
| S-EPMC6804881 | biostudies-literature
Project description:The oncogenic PIM1 kinase has been implicated as a cofactor for c-MYC in prostate carcinogenesis. In this study, we show that in human prostate tumors, coexpression of c-MYC and PIM1 is associated with higher Gleason grades. Using a tissue recombination model coupled with lentiviral-mediated gene transfer we find that Pim1 is weakly oncogenic in naive adult mouse prostatic epithelium. However, it cooperates dramatically with c-MYC to induce prostate cancer within 6-weeks. Importantly, c-MYC/Pim1 synergy is critically dependent on Pim1 kinase activity. c-MYC/Pim1 tumors showed increased levels of the active serine-62 (S62) phosphorylated form of c-MYC. Grafts expressing a phosphomimetic c-MYCS62D mutant had higher rates of proliferation than grafts expressing wild type c-MYC but did not form tumors like c-MYC/Pim1 grafts, indicating that Pim1 cooperativity with c-MYC in vivo involves additional mechanisms other than enhancement of c-MYC activity by S62 phosphorylation. c-MYC/Pim1-induced prostate carcinomas show evidence of neuroendocrine (NE) differentiation. Additional studies, including the identification of tumor cells coexpressing androgen receptor and NE cell markers synaptophysin and Ascl1 suggested that NE tumors arose from adenocarcinoma cells through transdifferentiation. These results directly show functional cooperativity between c-MYC and PIM1 in prostate tumorigenesis in vivo and support efforts for targeting PIM1 in prostate cancer.
| S-EPMC2861731 | biostudies-other
Project description:Enhancing cardiomyocyte survival is crucial to blunt deterioration of myocardial structure and function following pathological damage. PIM1 (Proviral Insertion site in Murine leukemia virus (PIM) kinase 1) is a cardioprotective serine threonine kinase that promotes cardiomyocyte survival and antagonizes senescence through multiple concurrent molecular signaling cascades. In hematopoietic stem cells, PIM1 interacts with the receptor tyrosine kinase c-Kit upstream of the ERK (Extracellular signal-Regulated Kinase) and Akt signaling pathways involved in cell proliferation and survival. The relationship between PIM1 and c-Kit activity has not been explored in the myocardial context. This study delineates the interaction between PIM1 and c-Kit leading to enhanced protection of cardiomyocytes from stress. Elevated c-Kit expression is induced in isolated cardiomyocytes from mice with cardiac-specific overexpression of PIM1. Co-immunoprecipitation and proximity ligation assay reveal protein-protein interaction between PIM1 and c-Kit. Following treatment with Stem Cell Factor, PIM1-overexpressing cardiomyocytes display elevated ERK activity consistent with c-Kit receptor activation. Functionally, elevated c-Kit expression confers enhanced protection against oxidative stress in vitro. This study identifies the mechanistic relationship between PIM1 and c-Kit in cardiomyocytes, demonstrating another facet of cardioprotection regulated by PIM1 kinase.
| S-EPMC7563506 | biostudies-literature
Project description:The Pim proteins are a family of highly homologous protein serine/threonine kinases that have been found to be overexpressed in cancer. Elevated levels of Pim1 kinase were first discovered in human leukemia and lymphomas. However, more recently Pim1 was found to be increased in solid tumors, including pancreatic and prostate cancers, and has been proposed as a prognostic marker. Although the Pim kinases have been identified as oncogenes in transgenic models, they have weak transforming abilities on their own. However, they have been shown to greatly enhance the ability of other genes or chemical carcinogens to induce tumors. To explore the role of Pim1 in prostate cancer, we generated conditional Pim1 transgenic mice, expressed Pim1 in prostate epithelium, and analyzed the contribution of PIM1 to neoplastic initiation and progression. Accordingly, we explored the effect of PIM1 overexpression in 3 different settings: upon hormone treatment, during aging, and in combination with the absence of one Pten allele. We have found that Pim1 overexpression increased the severity of mouse prostate intraepithelial neoplasias (mPIN) moderately in all three settings. Furthermore, Pim1 overexpression, in combination with the hormone treatment, increased inflammation surrounding target tissues leading to pyelonephritis in transgenic animals. Analysis of senescence induced in these prostatic lesions showed that the lesions induced in the presence of inflammation exhibited different behavior than those induced in the absence of inflammation. While high grade prostate preneoplastic lesions, mPIN grades III and IV, in the presence of inflammation did not show any senescence markers and demonstrated high levels of Ki67 staining, untreated animals without inflammation showed senescence markers and had low levels of Ki67 staining in similar high grade lesions. Our data suggest that Pim1 might contribute to progression rather than initiation in prostate neoplasia.
| S-EPMC3614961 | biostudies-literature
Project description:BackgroundThe current therapy for glioblastoma multiforme (GBM), the most aggressive and common primary brain tumor of adults, involves surgery and a combined radiochemotherapy that controls tumor progression only for a limited time window. Therefore, the identification of new molecular targets is highly necessary. Inhibition of kinases has become a standard of clinical oncology, and thus the oncogenic kinase Pim1 might represent a promising target for improvement of GBM therapy.MethodsExpression of Pim1 and associated signaling molecules was analyzed in human GBM samples, and the potential role of this kinase in patients' prognosis was evaluated. Furthermore, we analyzed the in vivo role of Pim1 in GBM cell growth in an orthotopic mouse model and examined the consequences of Pim1 inhibition in vitro to clarify underlying pathways.ResultsIn comparison with normal brain, a strong upregulation of Pim1 was demonstrated in human GBM samples. Notably, patients with short overall survival showed a significantly higher Pim1 expression compared with GBM patients who lived longer than the median. In vitro experiments with GBM cells and analysis of patients' GBM samples suggest that Pim1 regulation is dependent on epidermal growth factor receptor. Furthermore, inhibition of Pim1 resulted in reduced cell viability accompanied by decreased cell numbers and increased apoptotic cells, as seen by elevated subG1 cell contents and caspase-3 and -9 activation, as well as modulation of several cell cycle or apoptosis regulatory proteins.ConclusionsAltogether, Pim1 could be a novel therapeutic target, which should be further analyzed to improve the outcome of patients with aggressive GBM.
| S-EPMC4288523 | biostudies-literature