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
| Autor: | Kin-Mang Lau, Queeny Kwan Yi Chan, Fanny Man Ting Ma, Ka Fai To, Chi-Fai Ng, Jenny Tian Xia |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Gs alpha subunit MAP Kinase Signaling System GTP-Binding Protein alpha Subunits Gi-Go Biology Receptors G-Protein-Coupled Adenylyl cyclase 03 medical and health sciences chemistry.chemical_compound Humans Gene silencing Receptor Cell Proliferation Mitogen-Activated Protein Kinase 1 Cell growth Cell Cycle Prostatic Neoplasms Estrogens Cell migration Cell Biology Cell cycle Cell biology 030104 developmental biology Receptors Estrogen chemistry Filopodia Adenylyl Cyclases |
| Zdroj: | Experimental Cell Research. 350:199-209 |
| ISSN: | 0014-4827 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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