Abstract 3989: P-Cadherin overexpression modulates insulin-like growth factor signaling in oral squamous carcinoma cells.
Authors: Lysne Desseree , Perkins Michelle , Johns James , Van Dam Matthew , Cuevas Darren , Lawson Kathryn 
Published: August 2014

Abstract
Altered expression of cadherin cell adhesion proteins is a frequent occurrence in epithelial tumor development. P-cadherin, a component of normal epithelia, has been ascribed both causative and preventive roles in tumor development, contingent upon the tissue of origin. In oral epithelia, histological studies demonstrate an upregulation of P-cadherin during dysplasia, and a subsequent loss of P-cadherin in later stage oral squamous carcinomas. A possible mechanism by which P-cadherin may modulate tumor development is via alterations in ligand-mediated signaling of receptor tyrosine kinases, a phenomenon that has previously been demonstrated for both E- and N-cadherin. To better understand the role that P-cadherin plays in tumor development, retroviral transduction was used to deplete or overexpress P-cadherin in two oral squamous carcinoma cell lines. Six growth factors were independently utilized to screen for P-cadherin-dependent alterations in signaling, with the greatest effects occurring in response to insulin-like growth factor (IGF) and fibroblast growth factor (FGF). The increased level of P-cadherin in IGF-treated cells greatly altered the kinetics of mitogen-activated protein kinase (MAPK) signaling, but had little direct effect on the activation of the phosphoinositide 3-kinase (PI3K) pathway. P-cadherin overexpression increased steady-state levels of Snai1 protein, with further increases noted upon IGF administration. Inhibition of either MAPK or PI3K signaling pathways in P-cadherin overexpressing cells resulted in decreased Snai1 expression. Ser-9 phosphorylation of GSK-3β was unchanged after IGF treatment, suggesting P-cadherin contributes to Snai1 stability independent of GSK3β activity. P-cadherin over-expressing cells treated with IGF showed a time-dependent decrease in P-cadherin levels. This decrease was accompanied by a decrease in detectable levels of immunofluorescence staining of P-cadherin at cell borders. The internalization of P-cadherin could be inhibited by treatment with dynasore, a dynamin inhibitor. Also, increases in motility were found in P-cadherin overexpressing cells compared to normal cells. Our data suggests that the increase in P-cadherin seen in early oral cancer may promote tumor aggressiveness by altering cell behavior, and increasing EMT- related signaling. The contribution of P-cadherin to tumor development may be helpful in identifying biological targets for oral cancer therapies in dysplastic tissue.
Citation Format: Desseree Lysne, Michelle Perkins, James Johns, Matthew Van Dam, Darren Cuevas, Kathryn Lawson. P-Cadherin overexpression modulates insulin-like growth factor signaling in oral squamous carcinoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3989. doi:10.1158/1538-7445.AM2013-3989