Androgen deprivation therapy affects BCL-2 expression in human prostate cancer

Abstract

Abstract. BCL-2 is an integral protein of the external mitochondrial membrane that inhibits cell apoptotic death. We investigated the effect of androgen deprivation therapy (ADT) on BCL-2 expression in prostate cancer tissues. We studied BCL-2 expression in vivo in prostate cancer tissues obtained from patients who underwent radical prostatectomy after neoadjuvant ADT, by Northern and Western blot analysis, and immunohistochemistry. Moreover, gene transcriptional activity was also measured by nuclear run-on experiments. We demonstrated an increase of BCL-2 mRNA expression in patients who underwent neoadjuvant ADT for 1 month in comparison to patients who had not received any therapy. Moreover, we demonstrated that there were no significant modifications of BCL-2 mRNA levels in patients who underwent neoadjuvant ADT for 3 and 6 months. Furthermore, BCL-2 protein levels in patients who underwent neoadjuvant ADT for 1 month were upregulated in comparison to patients who had not received any therapy. Immunohistochemical analysis showed a strong positivity of prostate cells depending on ADT administration for 1 month. Finally, transcriptional activity was not modified in patients who underwent neoadjuvant ADT, suggesting the absence of hormonal regulation on BCL-2 gene expression at the transcriptional level. Our data show that short-term administration of ADT interferes with BCL-2 expression, suggesting that androgen-mediated mechanisms may act through BCL-2-mediated apoptotic pathways. Moreover, since short-term ADT administration does not interfere with BCL-2 expression at the transcriptional level, the androgen-mediated mechanisms involving BCL-2 pathways, probably act at the posttranscriptional level.

Current role of neoadjuvant and adjuvant systemic therapy for high-risk localized prostate cancer

“…Tumors containing the TMPRSS2-ERG fusion were found to have higher expression of proliferation-related genes at baseline, which was significantly reduced by ADT, suggesting androgen dependence despite the fusion event 25 . In contrast Bcl-2 protein expression in PC was found to increase after exposure to ADT, though this occurred despite a lack of increase in mRNA levels for the gene 26 . A study comparing tissue from patients exposed to neoadjuvant chemohormonal therapy to untreated prostatectomy specimens found that androgen receptor expression was not different, but steroidogenic enzyme expression (CYP17, SRD5A1) was increased 27 .…”

Molecular Pathways in Prostate Cancer

“…Bcl-2 has also been implicated in the development of androgen independent prostate cancer because of its increased expression in the advanced stages of disease ( 97 , 98 ). It is suggested that androgen-mediated mechanisms may act through Bcl-2-mediated apoptotic pathways ( 99 ).The overexpression of Bcl-2 in prostate cancer safeguards the tumor cells from apoptosis ( 100 , 101 ).…”

Bcl-2 expression is a poor predictor for hepatocellular carcinoma prognosis of andropause-age patients

“…Nevertheless, Ohigashi's data indicated that herbimycin A-sensitive tyrosine kinase(s) can regulate apoptosis and inhibit Bcl-2 expression in SC2G mouse androgen-dependent cells 32 . Fuzio et al 33 analyzed Bcl-2 expression in vivo in prostate cancer tissues obtained from patients who underwent radical prostatectomy after neoadjuvant androgen deprivation therapy (ADT). They found that short-term administration of ADT interferes with Bcl-2 expression, thereby suggesting that androgen-mediated mechanisms may act through Bcl-2-mediated apoptotic pathways.…”