The Sphingolipid Pathway in Colon Cancer Chemoprevention

该项目的长期目标是确定鞘脂途径在结肠癌发生中的作用， 建立该途径的元件作为有效的结肠癌化学预防的新靶点。结直肠 癌症是美国癌症相关死亡的第二大原因;因此， 药理学癌症预防策略至关重要。越来越多的证据表明， 因素，特别是脂肪（脂质），在结肠癌发生中是重要的。生物活性鞘脂可能是 调节炎症的前列腺素途径，在结肠癌发病机制中具有重要意义。鞘脂 神经酰胺、鞘氨醇和1-磷酸鞘氨醇（S1 P）等代谢物是一类新的脂质 调节细胞增殖、分化和存活的信使。鞘氨醇激酶1（SK 1）， 使鞘氨醇磷酸化形成S1 P的酶，是鞘脂介导功能的关键调节剂， 因为它不仅产生促生长、抗凋亡的信使S1 P，而且还降低促凋亡的水平。 凋亡神经酰胺和鞘氨醇。本实验室发现SK 1和S1 P介导环氧合酶-2 （考克斯-2）表达和前列腺素E2（PGE 2）的产生，以及SK 1 通过RNA干扰（RNAi）下调抑制由TNF-α诱导的考克斯-2表达和PGE 2产生。 细胞因子，并且S1 P刺激HT-29（人结肠癌细胞）中的考克斯-2表达和PGE 2产生。 大鼠肠上皮细胞SK 1过表达增加考克斯-2表达。值得注意的是，SK 1是 在人结肠肿瘤包括腺瘤和腺癌中上调。我们最近展示了 SK 1缺陷显著减少结肠肿瘤，包括癌前病变、腺瘤和癌症， 由氧化偶氮甲烷（AOM）诱导，一种在啮齿动物中确定的结肠致癌物。基于这些初步 根据这些数据，我们推测SK 1/S1 P通路可能在结肠癌的发生中起关键作用，并构成了结肠癌的发病机制。 结肠癌化学预防的新靶点。为了研究这一概念，我们提出以下建议 具体目的：1）评估SK 1/S1 P通路在结肠癌发生中的作用; 2）确定SK 1/S1 P通路在结肠癌发生中的作用。 SK 1/S1 P通路在调节考克斯-2表达中的作用和机制;和3）评估 在结肠癌化学预防中抑制SK 1/S1 P通路的优势。 从该项目中获得的结果将为SK 1/S1 P通路在以下方面的作用提供重要见解： 结肠癌发生和确定新的目标，为机制为基础的结肠癌化学预防，领先 未来的转化研究利用SK 1/S1 P途径在结肠癌发生。

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.