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Active DHEA uptake in the prostate gland correlates with aggressive prostate cancer.

ABSTRACT: Strategies for patient stratification and early intervention are required to improve clinical benefits for patients with prostate cancer. Here, we found that active DHEA utilization in the prostate gland correlated with tumor aggressiveness at early disease stages, and 3βHSD1 inhibitors were promising for early intervention. [3H]-labeled DHEA consumption was traced in fresh prostatic biopsies ex vivo. Active DHEA utilization was more frequently found in patients with metastatic disease or therapy-resistant disease. Genetic and transcriptomic features associated with the potency of prostatic DHEA utilization were analyzed to generate clinically accessible approaches for patient stratification. UBE3D, by regulating 3βHSD1 homeostasis, was discovered to be a regulator of patient metabolic heterogeneity. Equilin suppressed DHEA utilization and inhibited tumor growth as a potent 3βHSD1 antagonist, providing a promising strategy for the early treatment of aggressive prostate cancer. Overall, our findings indicate that patients with active prostatic DHEA utilization might benefit from 3βHSD1 inhibitors as early intervention.

SUBMITTER: Zhang X

PROVIDER: S-EPMC10721157 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Active DHEA uptake in the prostate gland correlates with aggressive prostate cancer.

Zhang Xuebin X Wang Zengming Z Huang Shengsong S He Dongyin D Yan Weiwei W Zhuang Qian Q Wang Zixian Z Wang Chenyang C Tan Qilong Q Liu Ziqun Z Yang Tao T Liu Ying Y Ren Ruobing R Li Jing J Butler William W Tang Huiru H Wei Gong-Hong GH Li Xin X Wu Denglong D Li Zhenfei Z

The Journal of clinical investigation 20231215 24

Strategies for patient stratification and early intervention are required to improve clinical benefits for patients with prostate cancer. Here, we found that active DHEA utilization in the prostate gland correlated with tumor aggressiveness at early disease stages, and 3βHSD1 inhibitors were promising for early intervention. [3H]-labeled DHEA consumption was traced in fresh prostatic biopsies ex vivo. Active DHEA utilization was more frequently found in patients with metastatic disease or therap ...[more]

PMID: 38099500

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Project description:ImportanceActive surveillance is an important option to reduce prostate cancer overtreatment, but it remains underutilized in many countries. Models from the United States show that greater use of active surveillance is important for prostate cancer screening to be cost-effective.ObjectivesTo perform an up-to-date, nationwide, population-based study on use of active surveillance for localized prostate cancer in Sweden.Design, setting, and participantsCross-sectional study in the National Prostate Cancer Register (NPCR) of Sweden from 2009 through 2014. The NPCR has data on 98% of prostate cancers diagnosed in Sweden and has comprehensive linkages to other nationwide databases. Overall, 32 518 men with a median age of 67 years were diagnosed with favorable-risk prostate cancer, including 4693, 15 403, and 17 115 men with very-low-risk (subset of the low-risk group) (clinical stage, T1c; Gleason score, ≤6; prostate-specific antigen [PSA], <10 ng/mL; PSA density <0.15 ng/mL/cm3; and <8-mm total cancer length in ≤4 positive biopsy cores), low-risk (including all men in the very-low-risk group) (T1-T2; Gleason score, ≤6; and PSA, <10 ng/mL), and intermediate-risk disease (T1-T2 with Gleason score, 7 and/or PSA, 10-20 ng/mL).ExposuresDiagnosis with favorable-risk prostate cancer.Main outcomes and measuresUtilization of active surveillance.ResultsThe use of active surveillance increased in men of all ages from 57% (380 of 665) to 91% (939 of 1027) for very-low-risk prostate cancer and from 40% (1159 of 2895) to 74% (1951 of 2644) for low-risk prostate cancer, with the strongest increase occurring from 2011 onward. Among men aged 50 to 59 years, 88% (211 of 240) with very-low-risk and 68% (351 of 518) with low-risk disease chose active surveillance in 2014. Use of active surveillance for intermediate-risk disease remained lower, 19% (561 of 3030) in 2014.Conclusions and relevanceActive surveillance has become the dominant management for low-risk prostate cancer among men in Sweden, with the highest rates yet reported and almost complete uptake for very-low-risk cancer. These data should serve as a benchmark to compare the use of active surveillance for favorable-risk disease around the world.

Project description:DNA methyltransferase (DNMT) is one of the major factors mediating the methylation of cancer related genes such as TGF-? receptors (T?Rs). This in turn may result in a loss of sensitivity to physiologic levels of TGF-? in aggressive prostate cancer (CaP). The specific mechanisms of DNMT's role in CaP remain undetermined. In this study, we describe the mechanism of TGF-?-mediated DNMT in CaP and its association with clinical outcomes following radical prostatectomy.We used human CaP cell lines with varying degrees of invasive capability to describe how TGF-? mediates the expression of DNMT in CaP, and its effects on methylation status of TGF-? receptors and the invasive capability of CaP in vitro and in vivo. Furthermore, we determined the association between DNMT expression and clinical outcome after radical prostatectomy. We found that more aggressive CaP cells had significantly higher TGF-? levels, increased expression of DNMT, but reduced T?Rs when compared to benign prostate cells and less aggressive prostate cancer cells. Blockade of TGF-? signaling or ERK activation (p-ERK) was associated with a dramatic decrease in the expression of DNMT, which results in a coincident increase in the expression of T?Rs. Blockade of either TGF-? signaling or DNMT dramatically decreased the invasive capabilities of CaP. Inhibition of TGF-? in an TRAMP-C2 CaP model in C57BL/6 mice using 1D11 was associated with downregulation of DNMTs and p-ERK and impairment in tumor growth. Finally, independent of Gleason grade, increased DNMT1 expression was associated with biochemical recurrence following surgical treatment for prostate cancer.Our findings demonstrate that CaP derived TGF-? may induce the expression of DNMTs in CaP which is associated with methylation of its receptors and the aggressive potential of CaP. In addition, DNMTs is an independent predictor for disease recurrence after prostatectomy, and may have clinical implications for CaP prognostication and therapy.

Project description:BackgroundThis study was undertaken to investigate the expression of guanyl nucleotide-releasing protein for Ras 3 (RasGRP3) in the cell lines and tissues in BPH and prostate cancer (PCa), as well as its associations with cancer invasion and prognosis in prostate carcinomas.MethodsExpression analysis of RasGRP3 was accomplished using immunohistochemical staining of PCa and BPH tissues. Pearson's χ2 test was used to analyze the association between RasGRP3 expression and specific clinical parameters. Survival and PSA relapse curves were evaluated using the Kaplan-Meier curves and log-rank tests, and the differences were assessed using the Cox regression methods. In addition, human PCa cell lines PC-3, DU145, LNCaP, PC3M-1E8, PC3M-2B4 and BPH-1 were examined for expression of RasGRP3 using western blot and quantitative polymerase chain reaction (Q-PCR) analysis. After PC-3 cells were transfected by small interfering RNA targeting RasGRP3, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and migratory assays were employed to determine the vitality and aggressive capability of tumor cell in vitro.ResultsExpression of RasGRP3 was significantly correlated (P=0.038 and P=0.021) with Gleason score (< or =6 versus > or =7) and T stage (T1-T2 versus T3-T4), respectively. PCa with RasGRP3-positive expression may increase the risk of PSA recurrence and decrease cancer-specific survival (P=0.0291 and P=0.0044). The expression of RasGRP3 was also associated with PSA recurrence and cancer-specific survival in univariate (P<0.001 and P<0.001) and multivariate analyses (P<0.001 and P=0.003). RasGRP3 mRNA and proteins were found to be positively expressed in PCa cell lines. There was higher expression of RasGRP3 in PC-3, DU145 and PC3M-1E8 than in LNCaP, PC3M-2B4 and BPH-1. Knockdown of RasGRP3 inhibited the proliferation, migration and invasion capabilities of PC-3 cells.ConclusionsThese data suggested that elevated RasGRP3 expression may play a key role in the malignant progression of PCa, especially in invasion and metastasis, and may be a potential marker of biochemical recurrence.

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Active DHEA uptake in the prostate gland correlates with aggressive prostate cancer.

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Active DHEA uptake in the prostate gland correlates with aggressive prostate cancer.

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