Checkpoint Kinase 2 Negatively Regulates Androgen Sensitivity and Prostate Cancer Cell Growth.

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. Cancer Res; 75(23); 1-13. ©2015 AACR.

Cancer research. 2015 Nov 16 [Epub ahead of print]

Huy Q Ta, Melissa L Ivey, Henry F Frierson, Mark R Conaway, Jaroslaw Dziegielewski, James M Larner, Daniel Gioeli

Departments of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia. , Departments of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia. , Department of Pathology, University of Virginia Health System, Charlottesville, Virginia. Cancer Center Member, University of Virginia, Charlottesville, Virginia. , Cancer Center Member, University of Virginia, Charlottesville, Virginia. Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia. , Cancer Center Member, University of Virginia, Charlottesville, Virginia. Department of Radiation Oncology, University of Virginia, Charlottesville, Virginia. , Cancer Center Member, University of Virginia, Charlottesville, Virginia. Department of Radiation Oncology, University of Virginia, Charlottesville, Virginia. , Departments of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia. Cancer Center Member, University of Virginia, Charlottesville, Virginia. 

PubMed

Read an article review by Bishoy Faltas, MD. 

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