Squamous cell carcinoma of the head and neck (SCCHN) is a major health problem worldwide, with over 45,000 new cases predicted to occur in the United States in 2009. Adjuvant therapies that can augment established treatments for SCCHN without causing significant additional morbidity are needed for this disease. Cyclooxygenase-2 (COX-2) inhibition has emerged as a potential adjuvant to established treatment regimens for SCCHN with this concept in mind, as COX-2 is known to be overexpressed in SCCHN. Celecoxib is a COX-2 specific NSAID with known antineoplastic activity against many human tumors, and is currently being used in clinical trials as a chemopreventive agent and adjuvant to established chemotherapy and radiation therapy protocols. The underlying mechanism of celecoxib toxicity remains poorly understood. Previous work from our laboratory has demonstrated marked inhibition of cell cycle progression through the G1 phase and induction of apoptosis following treatment with celecoxib in SCCHN, leading to cell cycle phase-specific toxicity to S and G2 phase cells and induction of p21waf1/cip1 with downstream inhibition of nuclear E2F activity. We therefore hypothesize that decreasing the observed cell cycle inhibition induced by celecoxib treatment may augment celecoxib toxicity by inducing cells to progress through more highly toxic cell cycle phases during celecoxib exposure. Further understanding of the mechanism of G1 arrest following celecoxib administration is therefore needed to effectively exploit this potential toxicity. MicroRNAs have been implicated in the control of cell cycle transition in several recent publications in stem cells and human cancers, and we believe that they may be involved in the cell cycle arrest seen after celecoxib treatment in SCCHN. To evaluate this hypothesis, SCCHN cells were exposed to celecoxib for 24 hours and G1 arrest was confirmed via flow cytometry. RNA and protein were extracted from celecoxib-treated and control cells and microRNA expression profiles were established by quantitative real-time PCR microarray analysis. Alterations in cell cycle gene expression across the cell cycle were assessed by similar microarray, and targets were confirmed by further western blotting and PCR analysis. Correlations between microRNA alterations in celecoxib-treated cells and cell cycle control genes were observed and extrapolated. These data provide a microRNA and cell cycle gene expression signature for celecoxib treatment in SCCHN, and further illustrate the potential role that microRNA expression plays in control of G1 cell cycle checkpoint kinetics and subsequent celecoxib toxicity.

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 3009.