Deregulated Sphingosine 1-Phosphate Signaling Contributes To A More Aggressive Phenotype In Oral Squamous Cell Carcinoma Cells

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Oral squamous cell carcinoma (OSCC) is the sixth most common cancer worldwide, accounting for more than 250,000 new cases each year. Early death usually occurs as a result of local invasion and regional lymph node metastases and overall five year mortality rates are approximately 50%. Novel therapeutic targets are urgently required. Sphingosine 1-phosphate (S1P) regulates many biological processes associated with tumour development and progression, with the specific effects of S1P being determined, in part, by the profile of receptor expression in tumor cells. Sphingosine kinase 1 (SphK1), an enzyme responsible for the production of S1P, has been reported to be overexpressed in OSCC tissues, but the effect of S1P on the behavior of OSCC cells and the expression of S1P receptors in OSCC has not been examined. The effect of S1P on OSCC cells was examined by treating OSCC cell lines in vitro. S1P inhibited the proliferation of OSCC cells but stimulated cell scattering in colony dispersal assays, causing colonies to disperse into single, highly migratory cells. S1P-induced cell migration was dependent on the MEK, ROCK and Rac-1 signaling pathways. Additionally, S1P enhanced tumor cell invasion in 3-dimensional organotypic invasion assays. S1P also protected OSCC cells from Cisplatin-induced apoptosis, as determined in clonogenic survival assays. Using QPCR, we show that OSCC cell lines express S1P receptors 1-3 and that the expression of S1P1 and S1P2 was significantly lower in 8/8 OSCC cell lines compared to normal oral keratinocytes (p<0.001), whilst S1P3 mRNA levels were significantly higher in 6/8 cell lines (p<0.001). S1P receptor expression was similarly deregulated in two dysplasia cell lines, suggesting that alterations in S1P signalling occur early in tumor progression. The results of the present study demonstrate that de-regulated S1P signaling contributes to a more motile, invasive and chemo-resistant phenotype in OSCC and indicate that the S1P-receptor axis may represent a promising target for therapy. Work is ongoing to examine the protein expression of S1P receptors in OSCC tissues and to determine the precise role of the S1P3 receptor in mediating the tumor promoting effects of S1P in OSCC cells. Citation Format: Steven Johnson, Lee Fah Yap, Sathya Narayanan, Ian Paterson. Deregulated sphingosine 1-phosphate signaling contributes to a more aggressive phenotype in oral squamous cell carcinoma 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 3988. doi:10.1158/1538-7445.AM2013-3988