The Sphingolipid Pathway in Colon Cancer Chemoprevention

结肠癌化学预防中的鞘脂通路

基本信息

批准号：
7580701
负责人：
TOSHIHIKO KAWAMORI
金额：
$ 30.61万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7580701
关键词：
Aberrant crypt foci Adenocarcinoma Adverse effects Animal Model Apoptosis Apoptotic Azoxymethane Beds Cancer Etiology Cancer Model Carcinogens Cardiovascular Physiology Cardiovascular system Cell Line Cell Proliferation Cells Ceramides Cessation of life Chemoprevention Chemopreventive Agent Clinical Colon Colon Carcinoma Colonic Neoplasms Colorectal Cancer Coxibs Data Development Dietary Factors Dinoprostone Down-Regulation Elements Endothelial Cells Enzymes Epithelial Cells Epoprostenol Fatty acid glycerol esters Future Goals Growth HT29 Cells Human Hypertension In Vitro Inflammation Intestines Knock-out Laboratories Laboratory Finding Lesion Lipids MAP Kinase Gene MAPK8 gene Malignant Neoplasms Measures Mediating Metastatic to Modeling Mus Pathogenesis Pathway interactions Play Prevention strategy Process Production Property Prostaglandins Prostaglandins I RNA RNA Interference Rattus Rodent Role SPHK1 enzyme Scheme Screening procedure Side Sphingolipids Sphingosine Sphingosine-1-Phosphate Receptor Staging Stroke System TNF gene Technology Testing Therapeutic Toxic effect Transgenic Mice Translating Translational Research Tumor Tissue Umbilical vein Work adenoma base cancer cell cancer chemoprevention cancer prevention carcinogenesis colon carcinogenesis cyclooxygenase 2 cytokine in vivo inhibitor/antagonist insight macrophage novel overexpression public health relevance response sphingosine 1-phosphate sphingosine kinase tumorigenesis

项目摘要

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.

描述（由申请人提供）：该项目的长期目标是定义鞘脂途径在结肠癌发生中的作用，并确定该途径的元素作为有效结肠癌化学预防的新靶标。结直肠癌是美国与癌症相关死亡的第二大原因。因此，对新颖，有效的药理学预防策略的识别至关重要。积累的证据表明，饮食因素，尤其是脂肪（脂质）在结肠癌发生中很重要。生物活性鞘脂可能是调节炎症的前列腺素途径的关键，这在结肠癌发病机理中很重要。鞘脂代谢物，例如神经酰胺，鞘氨酸和1-磷酸盐（S1P）是一种调节细胞增殖，分化和存活的新型脂质使者。鞘氨醇激酶1（SK1）是磷酸化鞘氨醇形成S1P的酶，是鞘脂介导功能的关键调节剂，因为它不仅会产生促生长的抗凋亡剂量S1P，而且还会降低促凋亡的陶器陶器和丙糖苷的水平。 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.大鼠肠上皮细胞中的SK1过表达增加了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被上调。我们最近证明，SK1缺乏症可显着降低结肠肿瘤，包括甲氧基甲烷（AOM）诱导的腺苷瘤和癌症，这是啮齿动物中已建立的结肠癌。基于这些初步数据，我们假设SK1/S1P途径可能在结肠癌发生中起关键作用，并且构成了针对结肠癌的化学预防的新靶标。为了研究这个概念，我们提出以下特定目的：1）评估SK1/S1P途径在结肠癌发生中的作用； 2）确定SK1/S1P途径在调节COX-2表达中的作用和机制； 3）评估结肠癌化学预防中SK1/S1P途径抑制的优势。从该项目获得的结果将为SK1/S1P途径在结肠癌发生中的作用提供重要见解，并确定基于机制的结肠癌化学预防的新颖目标，从而导致未来的转化研究利用结肠癌中的SK1/S1P途径。公共卫生相关性：最常见的可预防癌症是大肠癌。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，我们检查了鞘脂途径是否介导结肠癌的发展，并试图将基准结果转化为床边的临床化学预防措施。