COX-independent Antineoplastic Effects of Sulindac in Oral Cancer are Mediated by Survivin Down-regulation

Background: Cyclooxygenase (COX) inhibitors are reported to exert anti-proliferative and pro-apoptotic effects on cancer. The effects of COX inhibitors on oral squamous cell carcinoma (SCC) and survivin expression were assessed. Materials and Methods: Primary oral SCC were analyzed immunohistochemically, and oral SCC cell lines were assessed using RT-PCR, Western blot, cell proliferation and apoptosis assays, following treatment with various COX inhibitors, SiRNA against survivin, or survivin forced expression. Results: Survivin was expressed in all studied tumors. SiRNA against survivin or treatment with sulindac, but not other COX inhibitors, decreased survivin expression and tumor cell proliferation and increased apoptosis. Forced expression of survivin attenuated sulindac's effects. Conclusion: Survivin is implicated as a marker and treatment target in oral SCC, inhibition of which causes reduction of cell proliferation and induction of apoptosis. Down-regulation of survivin expression by sulindac provides an explanation for its antineoplastic effects.