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.
Results
The addition of HA, but not HA plus anti-CD44 antibody, resulted in increased Rho kinase and PI-3 kinase activity. Results of immunoblotting studies demonstrated that HA promotes Rho kinase-mediated myosin phosphatase phosphorylation and PI-3 kinase-mediated AKT phosphorylation. Hyaluronan was shown to promote migration and increased matrix metalloproteinase secretion through Rho kinase-mediated signaling. Hyaluronan 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 by HNSCC. 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.