Bcl-2 Expression as a Predictive Marker of Hormone-Refractory Prostate Cancer Treated with Taxane-Based Chemotherapy

Abstract

Purpose: Bcl-2 inhibits apoptosis, and its overexpression is associated with hormone refractory prostate cancer (HRPC). Bak and Bax are in the Bcl-2 family and counteract the antiapoptotic function of Bcl-2. Taxane-induced (paclitaxel and its analogue docetaxel) phosphorylation of Bcl-2 abolishes the potential antiapoptotic effect of Bcl-2. We hypothesized that (a) survival benefit in HRPC patients treated with taxanes is determined by the presence of Bcl-2 protein and (b) altered expression of Bak and Bax protein caused by genetic mutation is associated with biological aggressiveness of prostate cancer. Experimental Design: Forty localized prostate cancer and 30 HRPC cases were used in this study. Surgical specimens of localized prostate cancer and biopsy specimens of HRPC were used for immunostaining of Bcl-2, Bak, and Bax as well as DNA extraction. Mutations in the Bak and Bax genes were screened by single-strand conformational polymorphism, and confirmed by direct DNA sequencing. Results: Bcl-2^positive HRPC showed longer cause-specific survival in comparison with the counterparts. Multivariate analysis revealed that the level of Bcl-2 expression before treatment with taxane-based chemotherapy was an independent predictor for cause-specific survival (P < 0.01) and baseline prostate-specific antigen level was an independent predictor for progression-free survival (P < 0.01). Bax gene mutation was found in only one HRPC specimen.Conclusions: Bcl-2 expression in addition to prostate-specific antigen measurement before treatment could identify HRPC patients who may benefit from taxane-based chemotherapy. Mutation of the Bak and Bax genes is a rare event in prostate cancer.

An androgen-regulated miRNA suppresses Bak1 expression and induces androgen-independent growth of prostate cancer cells

“…Bak1 expression has also been reported to be associated with the progression of CaP. In a clinical study, Bak1 was detected in 77.5% primary and untreated localized CaP, but in only 33% hormone-refractory CaPs (37). Therefore, downregulation of Bak1 by miR-125b may contribute to disease progression and resistance to treatment in CaP.…”

Effect of DJ-1 overexpression on the proliferation, apoptosis, invasion and migration of laryngeal squamous cell carcinoma SNU-46 cells through PI3K/AKT/mTOR

“…However, some studies have found that the DJ-1 gene is closely related to tumor as well. Several studies found that DJ-1 protein overexpression is present in a variety of tumors such as breast cancer, non-small cell lung cancer, esophageal squamous cell carcinoma and prostate cancer, and this overexpression is related to proliferation, metastasis and poor prognosis of malignant tumors (6)(7)(8)(9)(10). Currently, carcinogenic DJ-1 gene downstream molecular signaling network and transduction mechanism remain unclear, and the role of the DJ-1 gene in the tumor formation and growth process is also unclear.…”

Androgen Action During Prostate Carcinogenesis

“…Elevated Bcl-2 expression is implicated in a variety of human malignancies, including prostate cancer (85,86). Whereas Bcl-2 expression is positive in most CRPCs, only approximately 30% androgen-dependent prostate cancers express low levels of Bcl-2, suggesting that Bcl-2 may contribute to the development of CRPC (87)(88)(89). It has been shown that androgens suppress Bcl-2 expression but the underlying mechanism is still unclear.…”

“…Bak1 is another member of the BH3 family, which is also known to be regulated by androgens (91 (89). The suppression of Bak1 expression by androgens is mediated by a microRNA.…”