title: Checkpoint Kinase 2 Negatively Regulates Androgen Sensitivity and Prostate Cancer Cell Growth.
abstract: 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.
authors.affiliation: Departments of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia.
authors.forename: Huy Q
authors.initials: HQ
authors.lastname: Ta
authors.affiliation: Departments of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Ivey
authors.affiliation: Department of Pathology, University of Virginia Health System, Charlottesville, Virginia. Cancer Center Member, University of Virginia, Charlottesville, Virginia.
authors.forename: Henry F
authors.initials: HF
authors.lastname: Frierson
authors.affiliation: Cancer Center Member, University of Virginia, Charlottesville, Virginia. Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Conaway
authors.affiliation: Cancer Center Member, University of Virginia, Charlottesville, Virginia. Department of Radiation Oncology, University of Virginia, Charlottesville, Virginia.
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Dziegielewski
authors.affiliation: Cancer Center Member, University of Virginia, Charlottesville, Virginia. Department of Radiation Oncology, University of Virginia, Charlottesville, Virginia.
authors.forename: James M
authors.initials: JM
authors.lastname: Larner
authors.affiliation: Departments of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia. Cancer Center Member, University of Virginia, Charlottesville, Virginia. dgg3f@virginia.edu.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gioeli
mesh_terms: D000728:Androgens / Q000378:metabolism*; D016203:CDC2 Protein Kinase; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D064447:Checkpoint Kinase 2 / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D006801:Humans; D008297:Male; D064129:Prostatic Neoplasms, Castration-Resistant / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D020687:cdc25 Phosphatases / Q000378:metabolism
chemical_list: C410798:AR protein, human; D000728:Androgens; D011944:Receptors, Androgen; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases