Abstract
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.
Highlights
Prostate cancer is the most common cancer affecting men in the Western World and the second leading cause of cancer death among American men [1]
Expression of Gαt selectively blocks G protein-coupled receptors (GPCRs) signaling in prostate cancer cells In our study of prostate cancer cells, Gβγ signaling was manipulated by expressing recombinant Gαt, a specific inhibitor of Gβγ that binds free Gβγ and selectively prevents the activation of Gβγ effectors without interfering with Gα signaling [37, 39]
Since pertussis toxin exclusively uncouples Gi/o proteins from their receptors by catalyzing the ADP-ribosylation of the Gai/o subunits [40], these findings suggest that these GPCRs activate AKT and ERK in cancer cell lines primarily through Gβγ freed from Gi/o proteins
Summary
Prostate cancer is the most common cancer affecting men in the Western World and the second leading cause of cancer death among American men [1]. Androgen-receptor (AR) signaling can persist, despite low levels of circulating androgen; alternatively, any one of many signaling pathways controlled by receptor tyrosine kinases and G protein-coupled receptors (GPCRs) can become deregulated Such changes can allow prostate cancer growth to become androgen independent [4,5,6,7,8]. Suggests another source of androgen independent CRPCs may be a small subpopulation of cells that retain stem-like properties [9,10,11] These stem-like cells can propagate tumors, have a survival advantage, and escape current chemotherapies, suggesting their stem-like qualities allow them to persist, become drug-resistant, proliferate, and metastasize. These cells have been termed cancer stem cells (CSCs)
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