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G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) act in concert to regulate cell growth, proliferation, survival, and migration. Metabotropic GABA B receptor (GABA B R) is the GPCR for the main inhibitory neurotransmitter GABA in the central nervous system. Increased expression of GABA B R has been detected in human cancer tissues and cancer cell lines, but the role of GABA B R in these cells is controversial and the underlying mechanism remains poorly understood. Here, we investigated whether GABA B R hijacks RTK signaling to modulate the fates of human prostate cancer cells. RTK array analysis revealed that the GABA B R-specific agonist baclofen selectively induced the transactivation of EGFR in PC-3 cells. EGFR transactivation resulted in the activation of ERK1/2 by a mechanism that is dependent on G i/o protein and that requires matrix metalloproteinase-mediated proligand shedding. Positive allosteric modulators (PAMs) of GABA B R, such as CGP7930, rac-BHFF, and GS39783, can function as PAM agonists to induce EGFR transactivation and subsequent ERK1/2 activation. Moreover, both baclofen and CGP7930 promoted cell migration and invasion through EGFR signaling. In summary, our observations demonstrated that GABA B R transactivated EGFR in a ligand-dependent mechanism to promote prostate cancer cell migration and invasion, thus providing new insights into developing a novel strategy for prostate cancer treatment by targeting neurotransmitter signaling.

GABABR-Induced EGFR Transactivation Promotes Migration of Human Prostate Cancer Cells

GABA_BR-Induced EGFR Transactivation Promotes Migration of Human Prostate Cancer Cells