Progression of prostate cancer: multiple pathways to androgen independence.

Prostate cancer remains one of the most commonly diagnosed cancers and a leading cause of cancer death in men. Initially, prostate tumors respond to hormonal therapies, but androgen-independent tumors refractory to these therapies emerge. Identifying the mechanisms responsible for the emergence of androgen independence has been the subject of multiple studies. This article reviews the multiple pathways that have been shown to promote androgen independence, including a recently described mechanism that involves androgen receptor proteolysis to a constitutively active ligand-independent isoform. Identifying the underlying mechanisms of androgen independence is crucial in the design of appropriate therapies for hormonally refractive neoplasms.

Impairment of the DNA repair and growth arrest pathways by p53R2 silencing enhances DNA damage-induced apoptosis in a p53-dependent manner in prostate cancer cells.

p53R2 is a p53-inducible ribonucleotide reductase that contributes to DNA repair by supplying deoxynucleotide triphosphate pools in response to DNA damage. In this study, we found that p53R2 was overexpressed in prostate tumor cell lines compared with immortalized prostatic epithelial cells and that the protein was induced upon DNA damage. We investigated the effects of p53R2 silencing on DNA damage in LNCaP cells (wild-type p53). Silencing p53R2 potentiated the apoptotic effects of ionizing radiation and doxorubicin treatment as shown by increased sub-G(1) content and decreased colony formation. This sensitizing effect was specific to DNA-damaging agents. Comet assay and gamma-H2AX phosphorylation status showed that the decreased p53R2 levels inhibited DNA repair. Silencing p53R2 also reduced the levels of p21(WAF1/CIP1) at the posttranscriptional level, suggesting links between the p53-dependent DNA repair and cell cycle arrest pathways. Using LNCaP sublines stably expressing dominant-negative mutant p53, we found that the sensitizing effect of p53R2 silencing is mediated by p53-dependent apoptosis pathways. In the LNCaP sublines (R273H, R248W, and G245S) that have defects in inducing p53-dependent apoptosis, p53R2 silencing did not potentiate DNA damage-induced apoptosis, whereas p53R2 silencing was effective in a LNCaP subline (P151S) which retains the ability to induce p53-dependent apoptosis. This study shows that p53R2 is a potential therapeutic target that could be used to enhance the effectiveness of ionizing radiation or DNA-damaging chemotherapy in a subset of patients with prostate cancer.