Cigarette smoking is the most serious preventable risk factor affecting human health in the United States and is the most significant risk factor for the development of lung cancer. Lung cancer associated with the use of tobacco often displays distinct genetic changes when compared to lung cancer from non-smoking individuals with an increased frequency of mutations in the K-Ras oncogene. Due to the aggressive characteristics of lung cancers with a mutation in the K-Ras oncogene, it is important to understand how the K-Ras oncogene drives tumor progression in order to understand how to best treat it. Using samples from our pathology tumor bank, we have determined that sphingosine kinase 1 is upregulated in human lung cancer and have preliminary evidence that the K-Ras oncogene regulates sphingosine kinase 1 (SK1) activity. SK1 is the primary enzyme responsible for producing the lipid signaling molecule, sphingosine-1-phosphate (S1P). S1P is a lipid molecule that plays a significant role in cellular proliferation, cellular survival, and is necessary during pathological and developmental angiogenesis. Tumors are highly dependent on signaling pathways that regulate their proliferation, survival, and recruitment of blood vessels for progression which makes sphingosine-1-phosphate an interesting target for study and potential therapeutic intervention in human cancer. Therefore, we wish to investigate the role of SK1 in lung cancer progression and if K-Ras leads to an enhancement of S1P production to promote tumor progression. Using mouse embryonic fibroblasts (MEFs) from both wildtype and SK1 knockout mice we will be able to generate inducible oncogenic K-Ras cell lines that express the K-Ras oncogene upon tetracycline exposure. Using this strategy we will be able to determine if the expression of oncogenic K-Ras increases S1P production to increase proliferation, survival or endothelial cell recruitment. Second, we plan to cross SK1 knockout mice with a mouse model of lung carcinogenesis (KRasLA2 mice) and determine if there are differences in survival and tumor progression compared to wildtype. The KRasLA2 mouse model will help us understand how alterations in sphingolipid metabolism can influence the development of lung cancer.
This research will contribute significantly to public health by providing further treatment options for patients affected by lung cancer. In addition, this research will better our understanding of how lung cancer progresses and have implications for other forms of cancer as well.
|Gault, Christopher R; Eblen, Scott T; Neumann, Carola A et al. (2012) Oncogenic K-Ras regulates bioactive sphingolipids in a sphingosine kinase 1-dependent manner. J Biol Chem 287:31794-803|
|Gault, Christopher R; Obeid, Lina M (2011) Still benched on its way to the bedside: sphingosine kinase 1 as an emerging target in cancer chemotherapy. Crit Rev Biochem Mol Biol 46:342-51|