Prostate cancer is the second leading cause of
cancer death in American men, and curing metastatic disease remains a significant challenge. Nearly all patients with disseminated
prostate cancer initially respond to
androgen deprivation
therapy (ADT), but virtually all patients will relapse and develop incurable
castration-resistant
prostate cancer (CRPC). A high-throughput RNAi screen to identify signaling pathways regulating
prostate cancer cell growth led to our discovery that
checkpoint kinase 2 (CHK2) knockdown dramatically increased
prostate cancer growth and hypersensitized cells to low
androgen levels. Mechanistic investigations revealed that the effects of CHK2 were dependent on the downstream signaling
proteins CDC25C and CDK1. Moreover, CHK2 depletion increased
androgen receptor (AR) transcriptional activity on
androgen-regulated genes, substantiating the finding that CHK2 affects
prostate cancer proliferation, partly, through the AR. Remarkably, we further show that CHK2 is a novel AR-repressed gene, suggestive of a negative feedback loop between CHK2 and AR. In addition, we provide evidence that CHK2 physically associates with the AR and that cell-cycle inhibition increased this association. Finally, IHC analysis of CHK2 in
prostate cancer patient samples demonstrated a decrease in CHK2 expression in high-grade
tumors. In conclusion, we propose that CHK2 is a negative regulator of
androgen sensitivity and
prostate cancer growth, and that CHK2 signaling is lost during
prostate cancer progression to
castration resistance. Thus, perturbing CHK2 signaling may offer a new therapeutic approach for sensitizing CRPC to ADT and radiation.