The long-term goal of this project is to define the role of sphingolipid pathway in colon carcinogenesis and to establish elements of this pathway as novel targets for effective colon cancer chemoprevention. Colorectal cancer is the 2nd leading cause of cancer-related deaths in the US;thus, identification of novel, effective pharmacological cancer-prevention strategies is essential. Accumulating evidence suggests that dietary factors, especially fat (lipids), are important in colon carcinogenesis. Bioactive sphingolipids may be key in regulating the prostanoid pathway of inflammation, significant in colon cancer pathogenesis. Sphingolipid metabolites such as ceramide, sphingosine, and sphingosine 1-phosphate (S1P) are a new class of lipid messengers that regulate cell proliferation, differentiation, and survival. Sphingosine kinase 1 (SK1), the enzyme that phosphorylates sphingosine to form S1P, is a critical regulator of sphingolipid-mediated functions, as it not only produces the pro-growth, anti-apoptotic messenger S1P, but also decreases levels of pro- apoptotic ceramide and sphingosine. Our laboratory found that SK1 and S1P mediate cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production in response to cytokines, and that SK1 downregulation by RNA interfering (RNAi) inhibits COX-2 expression and PGE2 production induced by cytokines, and S1P stimulates COX-2 expression and PGE2 production in HT-29, human colon cancer cells. SK1 overexpression in rat intestinal epithelial cells increases COX-2 expression. It is noteworthy that SK1 is upregulated in human colon tumors including adenomas and adenocarcinomas. We recently demonstrated that SK1 deficiency significantly reduces colon tumors including preneoplastic lesions, adenomas and cancers induced by azoxymethane (AOM), an established colon carcinogen in rodents. Based on these preliminary data, we hypothesize that the SK1/S1P pathway may play a pivotal role in colon carcinogenesis and constitute a novel target for chemoprevention against colon cancer. To investigate this concept, we propose the following Specific Aims: 1) Assess the role of the SK1/S1P pathway in colon carcinogenesis;2) Determine the role and mechanism of the SK1/S1P pathway in regulating COX-2 expression;and 3) Assess the advantages of inhibition of the SK1/S1P pathway in colon cancer chemoprevention. The results obtained from this project will provide important insights into the role of the SK1/S1P pathway in colon carcinogenesis and identify novel targets for mechanism-based colon cancer chemoprevention, leading to future translational research exploiting the SK1/S1P pathway in colon carcinogenesis.

Public Health Relevance

The most common preventable cancer is colorectal cancer. We found that sphingolipids play a pivotal role in colon cancer by regulating inflammation. In this project, we examine whether the sphingolipid pathway mediates development of colon cancer and we attempt to translate the bench results to bed-side clinical chemopreventive measures.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Chemo/Dietary Prevention Study Section (CDP)
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Perloff, Marjorie
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University of Hawaii
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Shimizu, Yoshiko; Furuya, Hideki; Tamashiro, Paulette M et al. (2018) Genetic deletion of sphingosine kinase 1 suppresses mouse breast tumor development in an HER2 transgenic model. Carcinogenesis 39:47-55
Furuya, Hideki; Shimizu, Yoshiko; Tamashiro, Paulette M et al. (2017) Sphingosine kinase 1 expression enhances colon tumor growth. J Transl Med 15:120
Tamashiro, Paulette M; Furuya, Hideki; Shimizu, Yoshiko et al. (2014) Sphingosine kinase 1 mediates head & neck squamous cell carcinoma invasion through sphingosine 1-phosphate receptor 1. Cancer Cell Int 14:76
Snider, Ashley J; Ali, Wahida H; Sticca, Jonathan A et al. (2014) Distinct roles for hematopoietic and extra-hematopoietic sphingosine kinase-1 in inflammatory bowel disease. PLoS One 9:e113998
Furuya, Hideki; Wada, Masayuki; Shimizu, Yoshiko et al. (2013) Effect of sphingosine kinase 1 inhibition on blood pressure. FASEB J 27:656-64
Tamashiro, Paulette M; Furuya, Hideki; Shimizu, Yoshiko et al. (2013) The impact of sphingosine kinase-1 in head and neck cancer. Biomolecules 3:481-513
Rao, Chinthalapally V; Patlolla, Jagan M R; Cooma, Indrani et al. (2013) Prevention of familial adenomatous polyp development in APC min mice and azoxymethane-induced colon carcinogenesis in F344 Rats by ?-3 fatty acid rich perilla oil. Nutr Cancer 65 Suppl 1:54-60
Snider, Ashley J; Wu, Bill X; Jenkins, Russell W et al. (2012) Loss of neutral ceramidase increases inflammation in a mouse model of inflammatory bowel disease. Prostaglandins Other Lipid Mediat 99:124-30
Ponnusamy, Suriyan; Selvam, Shanmugam Panneer; Mehrotra, Shikhar et al. (2012) Communication between host organism and cancer cells is transduced by systemic sphingosine kinase 1/sphingosine 1-phosphate signalling to regulate tumour metastasis. EMBO Mol Med 4:761-75
Furuya, Hideki; Shimizu, Yoshiko; Kawamori, Toshihiko (2011) Sphingolipids in cancer. Cancer Metastasis Rev 30:567-76

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