Activation of GPR30 stimulates GTP-binding of Gαi1 protein to sustain activation of Erk1/2 in inhibition of prostate cancer cell growth and modulates metastatic properties

- GPR30 activation by G-1 activates Gαi1 to sustain Erk1/2 activation in PCa cells.
- Stimulations of AC-cAMP-PKA signaling block the G-1-induced cell growth inhibition.
- Molecular consequences of GPR30 activation by G-1 in PCa cells are demonstrated.
- Roles of GPR30 in controlling metastatic properties of PCa cells are revealed.

Previously, we reported that GPR30 activation by the receptor-specific, non-estrogenic ligand G-1 inhibited in vitro and in vivo growth of prostate cancer (PCa) cells via sustained Erk1/2 activation. Mechanism underlying the sustained Erk1/2 activation for PCa cell growth inhibition remains unclear. Here we report that G-1, through GPR30, activated Gαi1 proteins to sustain Erk1/2 activation but failed to activate adenylyl cyclase (AC) for cAMP production in PCa cells. The chemical-induced activation of AC-cAMP-PKA signaling attenuated Erk1/2 activity and blocked the cell growth inhibitory effects of G-1. Furthermore, PCa predominantly expressed Gαi1 proteins. Silencing of Gαi1 expression blocked the inhibitory effects of G-1 on PCa cell growth. By gene expression profiling, GPR30 activation by G-1 interfered expression of cell cycle regulators and machinery elements to modulate PCa cell growth and the RACGAP1 interactome to control metastatic properties. In this regard, we demonstrated that G-1 inhibited PCa cell migration and invasion with reduced formations of filopodia and stress fibers through a GPR30-dependent pathway. Taken together, our findings revealed the underlying mechanism for sustaining Erk1/2 activation upon GPR30 activation by G-1 in PCa cells and the GPR30-mediated pathways in controlling PCa cell growth and metastatic properties.