Abstract
It is important to identify novel and effective targets for cancer prevention and therapy against head and neck squamous cell carcinoma (HNSCC), one of the most lethal cancers. Accumulating evidence suggests that the bioactive sphingolipids, such as sphingosine-1-phosphate (S1P) and its generating enzyme, sphingosine kinase 1 (SphK1) play pivotal roles in several important biological functions including promoting tumor growth and carcinogenesis. However, roles of SphK1/S1P in HNSCC development and/or progression have not been defined previously. Therefore, in this study, we first analyzed the expression of SphK1 in human HNSCC tumor samples and normal head & neck tissues (n = 78 and 17, respectively) using immunohistochemistry. The data showed that SphK1 is overexpressed in all of the HNSCC tumors tested (stages I-IV). We next investigated whether SphK1 is necessary for HNSCC development. To define the role of SphK1/S1P in HNSCC development, we utilized 4-nitroquinoline-1-oxide (4-NQO)-induced HNSCC model in wild-type mice compared with SphK1(-/-) knockout (KO) mice. Remarkably, we found that the genetic loss of SphK1, which reduced S1P generation, significantly prevented 4-NQO-induced HNSCC carcinogenesis, with decreased tumor incidence, multiplicity, and volume when compared with controls. Moreover, our data indicated that prevention of 4-NQO-induced HNSCC development in SphK1(-/-) KO mice might be associated with decreased cell proliferation, increased levels of cleaved (active) caspase 3, and downregulation of phospho (active) AKT expression. Thus, these novel data suggest that SphK1/S1P signaling may play important roles in HNSCC carcinogenesis, and that targeting SphK1/S1P might provide a novel strategy for chemoprevention and treatment against HNSCC.