Abstract 4121: Hyaluronan promotes Rho kinase and PI-3 kinase signaling in head and neck cancer

Abstract

Abstract Objectives: Hyaluronan (HA) is a ligand for the transmembrane receptor CD44, which acts through multiple signaling pathways to influence cellular behavior. The objective of this study was to investigate whether HA and CD44 promote Rho kinase and phosphatidyl inositol-3 (PI-3) kinase mediated oncogenic signaling to alter cisplatin sensitivity and stimulate tumor cell proliferation, migration, and matrix metalloproteinase (MMP) secretion in head and neck squamous cell carcinoma (HNSCC). Design/Subjects: Laboratory investigation utilizing a HNSCC cell line, HSC-3. Interventions: Rho kinase and PI-3 kinase activity, myosin phosphatase and AKT phosphorylation, tumor cell growth, migration, and MMP secretion were measured in the presence or absence of HA, cisplatin, and inhibitors of Rho kinase and PI-3 kinase. Results: The addition of HA, but not HA plus anti-CD44 antibody, resulted in increased Rho kinase and PI-3 kinase activity. Immunoblotting studies demonstrated that HA promotes Rho kinase mediated myosin phosphatase phosphorylation and PI-3 kinase mediated AKT phosphorylation. HA was shown to promote migration and increased MMP secretion through Rho kinase mediated signaling. HA treatment promoted increased tumor proliferation and resulted in a 12-fold reduced ability of cisplatin to cause HNSCC cell death. On the other hand, the presence of Y-27632, a Rho kinase inhibitor, and LY-294002, a PI-3 kinase inhibitor, blocked HA-mediated cisplatin resistance. Conclusions: Our results suggest that HA and CD44 promote Rho kinase and PI-3 kinase mediated oncogenic signaling and cisplatin resistance. Perturbation of HA-CD44 mediated Rho kinase and PI-3 kinase signaling pathways may be a novel strategy to treat HNSCC. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4121.