The Sphingolipid Pathway in Colon Cancer Chemoprevention

描述（由申请人提供）：该项目的长期目标是确定鞘脂通路在结肠癌发生中的作用，并建立该通路的元素作为有效结肠癌化学预防的新靶点。结直肠癌是美国癌症相关死亡的第二大原因；因此，确定新的、有效的癌症预防药物策略是至关重要的。越来越多的证据表明，饮食因素，特别是脂肪（脂质），在结肠癌的发生中起重要作用。生物活性鞘脂可能是调节前列腺素炎症途径的关键，在结肠癌发病机制中具有重要意义。神经酰胺、鞘氨醇和鞘氨醇1-磷酸（S1P）等鞘脂代谢产物是一类调节细胞增殖、分化和存活的新型脂质信使。鞘磷脂激酶1 （SK1）是鞘脂介导功能的关键调节因子，它不仅能产生促生长、抗凋亡的信使S1P，还能降低促凋亡的神经酰胺和鞘磷脂的水平。本实验室发现SK1和S1P响应细胞因子介导环氧化酶-2 （COX-2）表达和前列腺素E2 （PGE2）产生，通过RNA干扰（RNAi）下调SK1抑制细胞因子诱导的COX-2表达和PGE2产生，S1P刺激HT-29结肠癌细胞COX-2表达和PGE2产生。大鼠肠上皮细胞中SK1过表达可增加COX-2的表达。值得注意的是，SK1在包括腺瘤和腺癌在内的人类结肠肿瘤中表达上调。我们最近证明，SK1缺乏可显著减少由偶氮甲烷（AOM）引起的结肠肿瘤，包括瘤前病变、腺瘤和癌症，偶氮甲烷是啮齿动物的一种结肠癌致癌物。基于这些初步数据，我们推测SK1/S1P通路可能在结肠癌发生过程中发挥关键作用，并构成结肠癌化学预防的新靶点。为了研究这一概念，我们提出以下具体目标：1)评估SK1/S1P通路在结肠癌发生中的作用；2)确定SK1/S1P通路在调节COX-2表达中的作用及机制；3)评估抑制SK1/S1P通路在结肠癌化学预防中的优势。该项目获得的结果将为了解SK1/S1P通路在结肠癌发生中的作用提供重要见解，并为基于机制的结肠癌化学预防提供新的靶点，从而为未来利用SK1/S1P通路在结肠癌发生中的转化研究提供指导。公共卫生相关性：最常见的可预防癌症是结肠直肠癌。我们发现鞘脂通过调节炎症在结肠癌中起关键作用。在这个项目中，我们研究鞘脂通路是否介导结肠癌的发展，并试图将实验结果转化为床边临床化学预防措施。

DESCRIPTION (provided by applicant): 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.