Inhibiting G protein βγ 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 Gβγ subunits. Inhibiting Gβγ 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 Gβγ 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, Gβγ 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 Gβγ in regulating prostate cancer stem-cell-like activities, and demonstrate that targeting Gβγ signaling is an effective approach in blocking prostate cancer progression and augmenting response to chemotherapy.