Abstract 4409: P-cadherin modulates signaling of multiple growth factor receptors and cellular aggressiveness in oral carcinoma cells

Aberrant expression of the epithelial cell adhesion protein P-cadherin has been observed to be independently causative and preventative with respect to tumor progression, depending on tissue type. Oral epithelial tumors have been shown to exhibit a unique signature of P-cadherin expression in which P-cadherin expression increases in dysplasia and is subsequently lost during malignancy. These studies suggest that early increases in P-cadherin expression may be critical events in tumor progression. Since E- and N-cadherin have been shown to physically interact with and modulate function of Epidermal Growth Factor (EGF) and Fibroblast Growth Factor (FGF) respectively, we hypothesized that P-cadherin could promote tumor development via its own interaction with receptor tyrosine kinases in a ligand-dependent manner. To identify functional interactions between P-cadherin and receptor tyrosine kinases, we retrovirally transduced two independently isolated oral squamous carcinoma cell lines to overexpress P-cadherin. Transduced cells were treated independently with one of seven different growth factors to identify alterations in mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling pathways. For all experiments, protein was collected over the course of six hours at multiple timepoints to identify fluctuations in signaling. Although P-cadherin did not alter AKT phosphorylation, it was found to alter MAPK signaling in both a positive and negative manner. The most robust alterations in MAPK signaling occurred in response to activation of Insulin-like Growth Factor (IGF), Epithelial Growth Factor (EGF), and Keratinocyte Growth Factor (KGF). P-cadherin overexpression also induced phenotypic changes. Behavioral assays revealed that P-cadherin expression increased motility, but decreased expression of invasive proteases MMP-9 and MMP-14. P-cadherin cells grown in serum-free media for 48 hours exhibited increased cell number compared to control cells. A cell proliferation analysis (MTT assay) indicated lower rates of proliferation in P-cadherin -overexpressing cells compared to controls. This data suggests that the increased cell number of serum-starved P-cadherin cells was due to increased survival, rather than proliferation. These results demonstrate that P-cadherin overexpression can modulate ligand-dependent growth factor signaling and alter those cellular characteristics most commonly associated with tumor aggressiveness. Since P-cadherin expression has been shown to increase early on in the development of tumors, our research may provide a possible mechanism as to how this increase may play a role in tumor progression during dysplasia. Citation Format: James Mar, Adam Robinson, Rachel Neville, Desseree Lysne, Kathryn Lawson. P-cadherin modulates signaling of multiple growth factor receptors and cellular aggressiveness in oral carcinoma cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4409. doi:10.1158/1538-7445.AM2014-4409