Implications of Bcl-2 and its interplay with other molecules and signaling pathways in prostate cancer progression

ABSTRACT

Introduction: Among several genetic alterations involved in the progression of prostate cancer, B cell lymphoma gene number 2 (BCL-2) is an important target molecule in the progression of androgen-independent prostate cancer (AIPC) after androgen ablation or castration. Nevertheless, the molecular mechanism of BCL-2 in prostate cancer progression remains elusive and controversial. In the current review, we discuss the critical role of BCL-2 in the carcinogenesis of prostate cancer with experimental evidences on the BCL-2 molecular networks in AIPC and androgen-dependent prostate cancer (ADPC) and subsequently suggest perspective research targeting BCL-2.

Areas covered: This review focused on the molecular implications of BCL-2 in association with other molecules and signaling pathways involved in the progression and carcinogenesis of prostate cancer.

Expert opinion: BCL-2 plays a pivotal role in the progression of AIPC than in ADPC since androgen represses BCL-2. BCL-2 acts as a pro-survival molecule in association with androgen-related signaling in the progression of ADPC, while BCL-2 upregulation, PTEN loss, PI3K/AKT phosphorylation and receptor tyrosine kinase (RTK) activation are primarily involved in AIPC. To identify more effective prostate cancer therapy, further mechanistic studies are required with BCL-2 inhibitors in AIPC and ADPC, considering a multi-target therapy against BCL-2 and its related signaling.

KEYWORDS:

• BCL-2
• androgen
• prostate cancer
• microRNAs
• PTEN
• AKT

Article highlights

• BCL-2 is upregulated in the progression of AIPC at advanced stages after androgen ablation or castration.

• BCL-2 plays a pivotal role in the progression of AIPC compared with ADPC since androgen represses BCL-2 as an important pro-survival protein of the BCL-2 family.

• BCL-2 protects prostate cancers from apoptosis through the combination of molecules and signaling pathways, such as in PTEN loss and p53 inactivation, PI3K/AKT phosphorylation, activation of RTK/STAT3/NF-κB, Ras/Raf1/MEK/ERK, microRNAs (miR-24, miR-31, miR-34, miR-195, miR-204, miR-205 and lncRNA MEG3), autophagy proteins (Beclin1 and AMBRA1) and other potent molecules (FKBP38/NR4A1/GAL3).

• Multi-target therapy against BCL2 and its related signaling may represent a potent therapeutic strategy for prostate cancer treatment since BCL-2 is closely associated with other related molecules and signaling pathways, and thus far, there are no effective clinical trials with BCL-2 inhibitor alone in prostate cancer.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government (MEST) (2014R1A2A10052872).