Received for publication September 25, 2006.
Revised October 18, 2006.
Accepted for publication October 18, 2006.

Human chorionic gonadotropin (hCG) modulates prostate cancer cell survival after irradiation or HMG CoA reductase inhibitor treatment

Abstract

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 96h. Treatment of cells with hCG followed by exposure to ionizing radiation enhanced radiosensitivity. Exposure of LNCaP cells to hCG promoted activation of ERBB1 via a G_i-, MEK1/2- and metalloprotease- dependent paracrine mechanism, effects that were further enhanced following radiation exposure, and which were causal in prolonged intense activation of poly-ADP ribsosylpolymerase 1 (PARP1). Inhibition of ERBB1, MEK1 or PARP1 function suppressed the radiosensitizing properties of hCG. Radiosensitization was also, in part, dependent upon JNK1/2 signaling. PARP1-dependent radiosensitization was suppressed by a pan caspase inhibitor and by knock down of apoptosis inducing factor expression. Inhibition of PI3 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 co-exposure 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 were abolished by co-expression 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 over-expression 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.

Key words: NGF/EGF, Gi family, Protein Kinases (other), G protein regulation, Cdc42, rho, rac, other small G proteins, MAP Kinase, RNA/siRNA, Mechanisms of cell killing/apoptosis, Membrane targets, Cholesterol metabolism/lipoproteins

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