Inhibiting G Protein Beta Gamma Signaling Blocks Prostate Cancer Progression And Enhances The Efficacy Of Paclitaxel

Aberrant activation of G protein-coupled receptors (GPCRs) is implicated in prostate cancer progression, but targeting them has been challenging because multiple GPCRs are involved in cancer progression. In this study, we tested the effect of blocking signaling via a hub through which multiple GPCRs converge the G-protein G beta gamma subunits. Inhibiting G beta gamma signaling in several castration-resistant prostate cancer cell lines (i.e. PC3, DU145 and 22Rv1), impaired cell growth and migration in vitro, and halted tumor growth and metastasis in nude mice. The blockade of G beta gamma signaling also diminished prostate cancer stem cell-like activities, by reducing tumorsphere formation in vitro and tumor formation in a limiting dilution assay in nude mice. Furthermore, G beta gamma blockade enhanced the sensitivity of prostate cancer cells to paclitaxel treatment, both in vitro and in vivo. Together, our results identify a novel function of G beta gamma in regulating prostate cancer stem-cell-like activities, and demonstrate that targeting G beta gamma signaling is an effective approach in blocking prostate cancer progression and augmenting response to chemotherapy.