The G-protein coupled receptors, Galanin receptors 1, 2 and 3 (GALR1, GALR2, GALR3, respectively), and their ligand Galanin (GAL) exert pro-proliferative functions in the CNS. GALR2 has been shown to promote clonal growth in small cell lung cancer cells. However galanin receptor expression, GAL secretion, signaling pathways involved or role in proliferation in epithelial cells have not been investigated. Objective: To explore the role of GAL and GALRs in proliferation in keratinocytes and oropharyngeal squamous cell carcinoma (SCC) cell lines. Methods: GAL secretion in SCC cell lines was quantified using a competitive ELISA. Galanin receptor expression was determined by immunoblot analysis and RT-PCR. Proliferation, MAPK activation was investigated in human SCC cell lines and immortalized keratinocytes in the presence of increasing anti-galanin or anti-GALR1 antibody concentrations. Rap1 and Rho activation were evaluated using a pull-down assay. Results: GALR1, GALR2 and GALR3 protein and mRNA expression and GAL secretion were detected in all immortalized keratinocytes and SCC cell lines screened. Removal of galanin with antibody showed a dose-dependent inhibition of proliferation, consistent with a pro-proliferative role for galanin. Specific inhibition of GALR1 and stimulation of GALR2 both enhanced proliferation in immortalized keratinocytes and UM-SCC-11A suggesting antagonistic roles for these receptors. GALR1 inhibits proliferation via rap1-mediated inhibition of MAPK, whereas GALR2 activates MAPK via rho activation. Conclusions: This is the first report of GALR1 expression and function in non-neuronal cells. GALR1 and GALR2 have antagonistic effects on proliferation in epithelial cells raising the possibility that inactivation or disregulation of GALR1 and overexpression of GALR2 can lead to uncontrolled proliferation and neoplastic transformation. This work is supported by NIDCR DE00452-01, NCI SPORE grant P50 CA97248, NIDCR K08 award DE014620-01A1 and NRSA Training Grant T32 DE07057.

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