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

Abstract

G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) act in concert to regulate cell growth, proliferation, survival, and migration. Metabotropic GABA receptor (GABAR) is the GPCR for the main inhibitory neurotransmitter GABA in the central nervous system. Increased expression of GABAR has been detected in human cancer tissues and cancer cell lines, but the role of GABAR in these cells is controversial and the underlying mechanism remains poorly understood. Here, we investigated whether GABAR hijacks RTK signaling to modulate the fates of human prostate cancer cells. RTK array analysis revealed that the GABAR-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 protein and that requires matrix metalloproteinase-mediated proligand shedding. Positive allosteric modulators (PAMs) of GABAR, 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 GABAR 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.

GABAB1e promotes the malignancy of human cancer cells by targeting the tyrosine phosphatase PTPN12

“…In contrast, other studies revealed that GABA B receptor activation promoted the invasive ability of prostate and renal cancer cells (Azuma et al, 2003;Inamoto et al, 2007) and the metastasis of mouse breast 4T1 cancer cells (Zhang et al, 2014). We have also recently reported that GABA B receptor induced epidermal growth factor (EGFR) transactivation and promoted the invasion of human prostate cancer cells (Xia et al, 2017). GABA B receptor is a G-protein-coupled receptor (GPCR) and is composed of GABA B1 (GB 1 ) and GABA B2 (GB 2 ) subunits (Pin et al, 2004), encoded by the GABBR1 and GABBR2 genes, respectively.…”

Morphine promotes tumorigenesis and cetuximab resistance via EGFR signaling activation in human colorectal cancer

“…Both receptors mediate important signaling events and are involved in various complex physiological processes including cellular growth and differentiation (Wang et al, 2018). It was found that GPCRs could activate RTKs in the absence of RTK ligands (Delcourt et al, 2007), a phenomenon called transactivation (Crudden et al, 2018; Xia et al, 2017). The activation of EGFR main downstream signal pathway is closely related to the drug resistance mechanism of EGFR monoclonal antibodies (Zhang et al, 2017).…”

Emerging Roles of G Protein-Coupled Receptors in Hepatocellular Carcinoma

“…Further, GPCRs can utilize receptor tyrosine kinases (RTKs) to mediate important cellular responses, such as proliferation, differentiation, and survival [ 8 ]. Depending on the receptor and cell type, GPCRs signaling involves transactivation of several different RTKs, such as insulin-like growth factor 1 receptor (IGF1R), epidermal growth factor receptor (EGFR), and platelet-derived growth factor receptor (PDGFR) [ 9 , 10 , 11 ]. Then, numerous growth factors use G proteins and associated signaling molecules that participate downstream of RTKs to signal to effectors.…”