Androgen inhibits the growth of carcinoma cell lines established from prostate cancer xenografts that escape androgen treatment

Joly-Pharaboz, Marie-Odile; Kalach, Jean-Jacques; Pharaboz, Julie; Chantepie, Jacqueline; Nicolas, Brigitte; Baille, Marie-Laurence; Ruffion, A.; Benahmed, Mohamed; André, Jean

doi:10.1016/j.jsbmb.2008.02.011

Cited by 7 publications

(7 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Based on previous studies, we utilized the LNCaP xenograft model to evaluate the effect of 5-Aza-CdR on the growth suppression of prostate cancer in castrated male mice. We observed that, within the initial 17 days, the xenograft tumor volumes were decreased in response to castration compared to the control, though the tumor volumes began to increase in the next stage, illustrating that the LNCaP xenograft model can mimic the course of the clinical states of the transition from initial androgen dependency to androgen independency, which is consistent with other reports [29,30]. 5-Aza-CdR treatment significantly suppressed tumor progression and delayed the regeneration of prostate cancer cells in the later stage compared to the castration treatment alone.…”

Section: Discussionsupporting

confidence: 92%

Demethylation of the miR-146a promoter by 5-Aza-2’-deoxycytidine correlates with delayed progression of castration-resistant prostate cancer

et al. 2014

View full text Add to dashboard Cite

BackgroundAndrogen deprivation therapy is the primary strategy for the treatment of advanced prostate cancer; however, after an initial regression, most patients will inevitably develop a fatal androgen-independent tumor. Therefore, understanding the mechanisms of the transition to androgen independence prostate cancer is critical to identify new ways to treat older patients who are ineligible for conventional chemotherapy.MethodsThe effects of 5-Aza-2’-deoxycytidine (5-Aza-CdR) on the viability and the apoptosis of the androgen-dependent (LNCaP) and androgen-independent (PC3) cell lines were examined by MTS assay and western blot analysis for the activation of caspase-3. The subcutaneous LNCaP xenografts were established in a nude mice model. MiR-146a and DNMTs expressions were analyzed by qRT-PCR and DNA methylation rates of LINE-1 were measured by COBRA-IRS to determine the global DNA methylation levels. The methylation levels of miR-146a promoter region in the different groups were quantified by the bisulfite sequencing PCR (BSP) assay.ResultsWe validated that 5-Aza-CdR induced cell death and increased miR-146a expression in both LNCaP and PC3 cells. Notably, the expression of miR-146a in LNCaP cells was much higher than in PC3 cells. MiR-146a inhibitor was shown to suppress apoptosis in 5-Aza-CdR-treated cells. In a castrate mouse LNCaP xenograft model, 5-Aza-CdR significantly suppressed the tumors growth and also inhibited prostate cancer progression. Meanwhile, miR-146a expression was significantly enhanced in the tumor xenografts of 5-Aza-CdR-treated mice and the androgen-dependent but not the androgen-independent stage of castrated mice. In particular, the expression of miR-146a was significantly augmented in both stages of the combined treatment (castration and 5-Aza-CdR). Additionally, the methylation percentage of the two CpG sites (−444 bp and −433 bp), which were around the NF-κB binding site at miR-146a promoter, showed the lowest methylation levels among all CpG sites in the combined treatment tumors of both stages.ConclusionUp-regulating miR-146a expression via the hypomethylation of the miR-146a promoter by 5-Aza-CdR was correlated with delayed progression of castration-resistant prostate cancers. Moreover, site-specific DNA methylation may play an important role in miR-146a expression in androgen-dependent prostate cancer progression to androgen-independent prostate cancer and therefore provides a potentially useful biomarker for assessing drug efficacy in prostate cancer.

show abstract

Section: Discussionsupporting

confidence: 92%

Demethylation of the miR-146a promoter by 5-Aza-2’-deoxycytidine correlates with delayed progression of castration-resistant prostate cancer

et al. 2014

View full text Add to dashboard Cite

show abstract

“…The mechanisms promoting the repair of DNA DSBs exhibit cell-cycle dependency with homology-directed repair occurring in S/G2 and NHEJ occurring throughout the cell-cycle phases where it is the predominant mechanism of repair in G1 (48). As previously reported, SPA induces PC cell growth arrest in G1 ( Figure 2B) (49,50); therefore, instead of HR, AR/ SPA-induced DSBs should primarily undergo repair by NHEJ. To evaluate NHEJ activity, we focused on a key regulatory component of NHEJ, DNA-dependent protein kinase, catalytic subunit, DNA-PKcs.…”

Section: Resultssupporting

confidence: 56%

Supraphysiological androgens suppress prostate cancer growth through androgen receptor–mediated DNA damage

Chatterjee¹,

Schweizer²,

Lucas³

et al. 2019

Journal of Clinical Investigation

View full text Add to dashboard Cite

Prostate cancer (PC) initially depends on androgen receptor (AR) signaling for survival and growth. Therapeutics designed to suppress AR activity serve as the primary intervention for advanced disease. However, supraphysiological androgen (SPA) concentrations can produce paradoxical responses leading to PC growth inhibition. We sought to discern the mechanisms by which SPA inhibits PC and to determine if molecular context associates with antitumor activity. SPA produced an ARmediated, dose-dependent induction of DNA double-strand breaks, G 0 /G 1 cell-cycle arrest, and cellular senescence. SPA repressed genes involved in DNA repair and delayed the restoration of damaged DNA, which was augmented by poly (ADPribose) polymerase 1 inhibition. SPA-induced double-strand breaks were accentuated in BRCA2-deficient patients with PC, and combining SPA with poly (ADP-ribose) polymerase or DNA-dependent protein kinase inhibition further repressed growth. Next-generation sequencing was performed on biospecimens from patients with PC receiving SPA as part of ongoing phase II clinical trials. Patients with mutations in genes mediating homology-directed DNA repair were more likely to exhibit clinical responses to SPA. These results provide a mechanistic rationale for directing SPA therapy to patients with PC who have AR amplification or DNA repair deficiency and for combining SPA therapy with poly (ADP-ribose) polymerase inhibition.

show abstract

“…These processes seem to be regulated, at least in part, by different mechanisms, given the observation in preclinical studies that their maximal stimulation occurs at different concentrations of testosterone, 31-33 with PSA production stimulated at higher testosterone concentrations than cell proliferation. If PSA is a marker of benign prostate cells and highly differentiated prostate cancer cells, then lower testosterone levels should correspond with lower PSA levels and more poorly differentiated cancer.…”

Section: Discussionmentioning

confidence: 99%

Testosterone Replacement Therapy and Risk of Favorable and Aggressive Prostate Cancer

Loeb

Folkvaljon

Damber

et al. 2017

JCO

View full text Add to dashboard Cite

PurposeThe association between exposure to testosterone replacement therapy (TRT) and prostate cancer risk is controversial. The objective was to examine this association through nationwide, population-based registry data.MethodsWe performed a nested case-control study in the National Prostate Cancer Register of Sweden, which includes all 38,570 prostate cancer cases diagnosed from 2009 to 2012, and 192,838 age-matched men free of prostate cancer. Multivariable conditional logistic regression was used to examine associations between TRT and risk of prostate cancer (overall, favorable, and aggressive).ResultsTwo hundred eighty-four patients with prostate cancer (1%) and 1,378 control cases (1%) filled prescriptions for TRT. In multivariable analysis, no association was found between TRT and overall prostate cancer risk (odds ratio [OR], 1.03; 95% CI, 0.90 to 1.17). However, patients who received TRT had more favorable-risk prostate cancer (OR, 1.35; 95% CI, 1.16 to 1.56) and a lower risk of aggressive prostate cancer (OR, 0.50; 95% CI, 0.37 to 0.67). The increase in favorable-risk prostate cancer was already observed within the first year of TRT (OR, 1.61; 95% CI, 1.10 to 2.34), whereas the lower risk of aggressive disease was observed after > 1 year of TRT (OR, 0.44; 95% CI, 0.32 to 0.61). After adjusting for previous biopsy findings as an indicator of diagnostic activity, TRT remained significantly associated with more favorable-risk prostate cancer and lower risk of aggressive prostate cancer.ConclusionThe early increase in favorable-risk prostate cancer among patients who received TRT suggests a detection bias, whereas the decrease in risk of aggressive prostate cancer is a novel finding that warrants further investigation.

show abstract

Androgen inhibits the growth of carcinoma cell lines established from prostate cancer xenografts that escape androgen treatment

Cited by 7 publications

References 25 publications

Demethylation of the miR-146a promoter by 5-Aza-2’-deoxycytidine correlates with delayed progression of castration-resistant prostate cancer

Demethylation of the miR-146a promoter by 5-Aza-2’-deoxycytidine correlates with delayed progression of castration-resistant prostate cancer

Supraphysiological androgens suppress prostate cancer growth through androgen receptor–mediated DNA damage

Testosterone Replacement Therapy and Risk of Favorable and Aggressive Prostate Cancer

Contact Info

Product

Resources

About