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Human Chorionic Gonadotropin Modulates Prostate Cancer Cell Survival after Irradiation or HMG CoA Reductase Inhibitor Treatment

Departments of Biochemistry (A.Y., W.H., D.H., H.Y., M.A.P., M.G., P.D.), Medicine (S.G.), and Radiation Oncology (K.V., M.P.H.), Virginia Commonwealth University, Richmond, Virginia; Departments of Pathology, Neurosurgery, and Urology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, New York (P.B.F.); and Division of Human Gene Therapy, Departments of Medicine, Pathology, and Surgery, and the Gene Therapy Center, University of Alabama at Birmingham, Birmingham, Alabama (D.T.C.)

The impact of human chorionic gonadotropin (hCG) on prostate carcinoma viability was investigated. Treatment of LNCaP and PC-3 cells with hCG modestly reduced cell viability within 96 h. Treatment of cells with hCG followed by exposure to ionizing radiation enhanced radiosensitivity. Exposure of LNCaP cells to hCG promoted activation of epidermal growth factor receptor (ERBB1) via a G_i-, mitogen-activated protein kinase kinase (MEK)1/2-, and metalloprotease-dependent paracrine mechanism, effects that were further enhanced after radiation exposure, and that were causal in prolonged intense activation of poly(ADP-ribose) polymerase (PARP). Inhibition of ERBB1, MEK1, or PARP1 function suppressed the radiosensitizing properties of hCG. Radiosensitization was also, in part, dependent upon c-Jun NH₂-terminal kinase 1/2 signaling. PARP1-dependent radiosensitization was suppressed by a pan-caspase inhibitor and by knockdown of apoptosis-inducing factor expression. Inhibition of phosphatidylinositol 3-kinase, expression of dominant-negative AKT, or treatment with the HMG CoA reductase inhibitor lovastatin suppressed AKT phosphorylation and enhanced the cytotoxic effects of hCG. The enhancing effect of lovastatin was reproduced by incubation with a geranylgeranyl transferase inhibitor and blocked by coexposure to geranylgeranyl pyrophosphate. Treatment with hCG and lovastatin decreased expression of BCL-_XL and XIAP, and increased expression of IB. The cytotoxic effects of hCG were enhanced by expression of dominant-negative IB, and they were abolished by coexpression of activated AKT. Expression of activated AKT maintained BCL-_XL levels in cells expressing dominant-negative IB. The promotion of hCG lethality by lovastatin was abolished by overexpression of BCL-_XL, and was dependent upon activation of caspase-9. Thus, hCG, in combination with radiation and lovastatin, may represent a novel approach to kill prostate cancer cells.

Address correspondence to: Dr. Paul Dent, Department of Biochemistry, 401 College St., Massey Cancer Center, Room 2-108, Box 980035, Virginia Commonwealth University, Richmond VA 23298-0035. E-mail: pdent{at}hsc.vcu.edu

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