Targeting Gbetagamma signaling to inhibit prostate tumor formation and growth.
Prostate cancer starts as androgen-dependent malignancy and responds initially to androgen ablative therapy. Beneficial effects of androgen ablation, however, are often temporary and the cancer reappears as androgen-independent tumor, suggesting the existence of additional factors responsible for progression of the disease. Attention has focused on receptor tyrosine kinases as the growth mediators of androgen-independent prostate cancer; overexpression of epidermal growth factor receptors or their ligand heparin-bound epidermal growth factor, for example, promotes transition to androgen independence. Emerging data demonstrate involvement of another class of cell membrane-anchored receptors, the heterotrimeric guanine-binding (G) protein-coupled receptors (GPCRs) in prostate cancer. In vitro, stimulation of many endogenous GPCRs induces mitogenic signaling and growth of prostate cancer cells. The GPCRs transduce mitogenic signals via activated G proteins in the form of Galpha-GTP and Gbetagamma subunits. Here, we show that expression of a Gbetagamma inhibitor peptide derived from carboxy terminus of G protein-coupled receptor kinase 2 obliterates serum-regulated prostate cancer cell growth in vitro and prevents prostate tumor formation in vivo. We also demonstrate that inhibition of Gbetagamma signaling retards growth of existing prostate tumors by inducing cell death. These data establish a central role for heterotrimeric G proteins in prostate cancer and suggest targeted inhibition of Gbetagamma signaling may serve as specific molecular therapy tool to limit pathologic growth of advanced prostate cancer.
Bookout
Angela L
AL
Department of Surgery, Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Finney
Amanda E
AE
Guo
Rishu
R
Peppel
Karsten
K
Koch
Walter J
WJ
Daaka
Yehia
Y
D002455:Cell Division; D045744:Cell Line, Tumor; D002470:Cell Survival; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics*; D044387:GTP-Binding Protein beta Subunits / Q000037:antagonists & inhibitors*; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D010446:Peptide Fragments / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000473:pathology / Q000628:therapy*; D051552:beta-Adrenergic Receptor Kinases
D044387:GTP-Binding Protein beta Subunits; D010446:Peptide Fragments; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases