Abstract 2958: Knockdown of Src expression dissolves resistance to TRAIL-induced apoptosis in oral cancer cells.

Abstract

Abstract A radical operation for advanced oral cancer results in malfunction of chewing, swallowing, and pronouncing etc. Nevertheless, the most standard therapy for oral cancer is a surgical resection because of its good outcome compared to radiation and chemotherapy. It is expected that treatment is less-invasive and effective against not only primary lesion but also metastatic sites or cells with metastatic potential. Because the acquisition of resistance to anoikis and apoptosis is considered as an essential event to successfully metastasize, we focused on the apoptotic signaling pathways mediated by natural death ligands. In this study, we have used oral squamous cell carcinoma (OSCC) cell lines with distinct metastatic potential and attempted to disclose their apoptosis sensitivity. More than half of the cells died under the low attachment culture condition in all OSCC cell lines with no relation between their metastatic potential, while other kind of cancer cell lines showed anoikis resistance. SAS cells established from human tongue squamous cell carcinoma showed modest sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), whereas SAS-T5 and SAS-L1 cells, a clone with high metastatic potential showed robust resistance. Fas ligand (Anti-Fas/CD95 monoclonal antibody) showed the similar trend of apoptosis induction as well as TRAIL, but TNF-α had no effect in these cells. We confirmed that the expression levels and the localization of TRAIL receptors were not correlated with TRAIL sensitivity. One of the mechanisms underlying the differences in resistance between these cell lines was an activity of Src kinase. Phosphorylated Src (Tyr 416), the active form, was upregulated in SAS-T5 and SAS-L1 cells compared to parental SAS cells. Src inhibitor PP2 suppressed cell proliferation in response to dependence on Src signaling. Downregulation of Src with siRNA made metastatic cells dissolve the resistance to TRAIL-induced apoptosis. These results suggest that combination therapy with TRAIL plus medicine inhibiting Src kinase may be a treatment strategy for oral squamous cell carcinoma. Citation Format: Tomohiro Hamakawa, Satoshi Hino, Koh-ichi Nakashiro, Hiroyuki Hamakawa. Knockdown of Src expression dissolves resistance to TRAIL-induced apoptosis in oral cancer 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 2958. doi:10.1158/1538-7445.AM2013-2958