TY - JOUR
T1 - Human chorionic gonadotropin modulates prostate cancer cell survival after irradiation or HMG CoA reductase inhibitor treatment
AU - Yacoub, Adly
AU - Hawkins, William
AU - Hanna, David
AU - Young, Hong
AU - Park, Margaret A.
AU - Grant, Mark
AU - Roberts, John D.
AU - Curiel, David T.
AU - Fisher, Paul B.
AU - Valerie, Kristoffer
AU - Grant, Steven
AU - Hagan, Michael P.
AU - Dent, Paul
PY - 2007
Y1 - 2007
N2 - 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 Gαi-, 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 NH 2-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 IκB. The cytotoxic effects of hCG were enhanced by expression of dominant-negative IκB, and they were abolished by coexpression of activated AKT. Expression of activated AKT maintained BCL-XL levels in cells expressing dominant-negative IκB. 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.
AB - 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 Gαi-, 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 NH 2-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 IκB. The cytotoxic effects of hCG were enhanced by expression of dominant-negative IκB, and they were abolished by coexpression of activated AKT. Expression of activated AKT maintained BCL-XL levels in cells expressing dominant-negative IκB. 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.
UR - http://www.scopus.com/inward/record.url?scp=33845875980&partnerID=8YFLogxK
U2 - 10.1124/mol.106.031153
DO - 10.1124/mol.106.031153
M3 - Article
C2 - 17050804
AN - SCOPUS:33845875980
VL - 71
SP - 259
EP - 275
JO - Molecular Pharmacology
JF - Molecular Pharmacology
SN - 0026-895X
IS - 1
ER -