Bcl-2 is a negative prognostic indicator in prostate cancer, implicated in the development of androgen independence and treatment resistance, and is overexpressed in hormone-refractory prostate cancer (HRPC).
In this study, a novel human BH3-only protein, Bcl-2-interacting mediator (Bim)gamma, was identified during our study of regulation of prostate cancer cell death by Bcl-2 family proteins.
Ionizing radiation caused induction NF kappa B activity and Bcl-2 protein expression in the radioresistant p53 null human prostate cancer cell line, PC-3.
Taken together, our results suggest that this Bax expression system might represent a useful gene therapy strategy when applied to the treatment of prostate cancer and its efficacy would be independent of the Bcl-2 status and androgen sensitivity of these cancers.
D-RNAi (Messenger RNA-antisense DNA interference), a novel posttranscriptional phenomenon of silencing gene expression by transfection of mRNA-aDNA hybrids, was originally observed in the effects of bcl-2 on phorbol ester-induced apoptosis in human prostate cancer LNCaP cells.
These results support a potential bcl-2 interference with the TGF-beta and androgen apoptotic signaling in prostate cancer cells by means of an antagonistic effect on caspase-1 activation.
In addition, these results provide a possible mechanistic basis for the up-regulation (derepression) of bcl-2 observed in hormone independent prostate cancers.
We investigated the role of the product of the prostate apoptosis response gene-4 (Par-4) and the product of the Wilms' tumor 1 gene (WT1) in the regulation of Bcl-2 expression in prostate cancer cell lines.
To clarify the basis for cell killing during prostate cancer radiotherapy, we determined the IR-induced expression of several apoptotic- (bax, bcl-2, survivin and PARP) and G1-cell cycle checkpoint- (p53 and p21(WAF1/Cip1)) related proteins, in both normal (PrEC-epithelial and PrSC-stromal) and malignant (LNCaP, DU-145 and PC-3; all epithelial) prostate cells.
Our data indicate that the combined treatment of Apo2L/TRAIL and CPT-11 achieves tumor control in prostate cancer tumors through regulation of Bcl-2 family proteins and potent activation of caspases.
This review discusses salient features of molecules such as, Bcl-2, Bcl-(XL), NF-kappaB, Akt, PTEN and Par-4 that play a significant role in the regulation of prostate cancer and focuses on the prospects of effectively utilizing their potential for the therapy of hormone-sensitive and hormone-resistant prostate cancer.
The current status and future direction of a number of antisense oligonucleotides targeting several genes, including BCL-2, BCL-XL, clusterin, the inhibitors of apoptosis (IAP) family, MDM2, protein kinase C-alpha, c-raf, insulin-like growth factor binding proteins and the AR, that have potential clinical use in prostate cancer are reviewed.
We focus on some key regulatory molecules, including the pro-apoptotic regulators p53, PTEN, caspases and Par-4, and the anti-apoptotic molecules Bcl-2, NF-kappaB and Akt, to discuss their roles in prostate cancer progression and their therapeutic implications in human prostate carcinoma.
The relationship of Bcl-2 expression in four prostate cancer cell lines, and the effect of modulating expression with a Bcl-2 antisense oligonucleotide (G3139, Genasense, oblimersen sodium, Genta Incorporated), to RT was examined.
Considering that elevated expression of bcl-xL and bcl-2 are frequent events in prostate cancer development and progression, the present studies support the use of ionizing radiation in combination with mda-7/IL-24 as a means of augmenting the therapeutic benefit of this gene in prostate cancer, particularly in the context of tumors displaying resistance to radiation therapy owing to bcl-2 family member overexpression.
These findings support the concept of the targeted suppression of Bcl-2 anti-apoptotic family members using multitarget inhibition strategies for prostate cancer, through the effective induction of apoptosis.