Novel and effective targets for cancer therapy and prevention are increasingly important in cancer research, especially for head and neck squamous cell carcinoma (HNSCC), which is one of the most lethal cancers. A potential target for this type of cancer might be sphingosine kinase 1 (SphK1) which phosphorylates sphingosine to form sphingosine-1-phosphate (S1P) because it is a critical regulator of sphingolipid-mediated functions and the SphK1/S1P pathway has been implicated in several important biological functions including inflammation and carcinogenesis. To investigate the potential of SphK1 as a target in head and neck cancer development, we used a 4-nitroquinoline-1-oxide (4-NQO)-induced carcinogenesis tongue model in SphK1 knockout mice. All mice were treated with 4-NQO at 40 μg/ml in drinking water for 14 weeks (untreated water was available thereafter, until the end of the experiment). All animals were sacrificed at 20 weeks and animal tongues were examined. We found that SphK1 positively stained in tongue cancer induced by 4-NQO in wild type mice, and 72% SphK1 KO mice developed tongue cancer, whereas 96% of the wild type mice did (P<0.05). Furthermore, tongue cancer volume was significantly decreased in SphK1 KO mice (P<0.05). To understand how SphK1 is responsible for decreasing tongue cancer, we used a BrdU incorporation assay to evaluate cell proliferation and used a cleaved caspase-3 immunohistochemistry assay to indicate apoptosis in tongue cancer tissues. We found that tongue cancers in SphK1 KO mice had significantly less cell proliferation and increased apoptosis compared to in wild type mice (P<0.01 and P<0.001, respectively). Assaying for sphingolipid profiles in mouse blood, we found that S1P was significantly reduced in SphK1 KO mice (P<0.001), and that C16-ceramide was also significantly reduced in SphK1 KO mice compared to wild type mice (P<0.05). These data are consistent with our previous results (Cancer Lett., 256: 101-111, 2007). We also found that 4-NQO-activated phospho-Akt was reduced in tongue cancers in SphK1 KO mice, suggesting that the SphK1/S1P pathway may be involved in PI3K-Akt-mTOR pathway in HNSCC development. Our data suggest that the SphK1/S1P pathway may mediate HNSCC development and that inhibition of this pathway may be an effective and novel target for chemoprevention against 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 5656.