Abstract
G protein–coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) act in concert to regulate cell growth, proliferation, survival, and migration. Metabotropic GABAB receptor (GABABR) is the GPCR for the main inhibitory neurotransmitter GABA in the central nervous system. Increased expression of GABABR has been detected in human cancer tissues and cancer cell lines, but the role of GABABR in these cells is controversial and the underlying mechanism remains poorly understood. Here, we investigated whether GABABR hijacks RTK signaling to modulate the fates of human prostate cancer cells. RTK array analysis revealed that the GABABR-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 Gi/o protein and that requires matrix metalloproteinase–mediated proligand shedding. Positive allosteric modulators (PAMs) of GABABR, 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 GABABR 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.
Footnotes
- Received December 14, 2016.
- Accepted April 14, 2017.
S.X. and C.H. contributed equally to this work.
The study was financially supported by grants from National Natural Science Foundation of China [Grants 31170790, 31225011, 31420103909, and 31371423]; start funding from The Ministry of Education, China, independent innovation research funding from Huazhong University of Science and Technology, Wuhan, China [Grant M2009047]; the Fundamental Research Funds for the Central Universities, China [Grant 0118170132/2016YXMS25]; the Natural Science Foundation of Hubei Province [Grant 2014CFA010]; the Program of Introducing Talents of Discipline to Universities from the Ministry of Education of China [Grant B08029]; and the Program for Changjiang Scholars and Innovative Research Team in University [Grant PCSIRT: IRT13016].
↵This article has supplemental material available at molpharm.aspetjournals.org.
- Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|