Chemoprevention via modulation of autophagy by sphingolipids

通过鞘脂调节自噬进行化学预防

基本信息

批准号：
7590890
负责人：
ALFRED Harrison MERRILL
金额：
$ 7.17万
依托单位：
GEORGIA INSTITUTE OF TECHNOLOGY
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：
2009-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7590890
关键词：
Affect Anabolism Antineoplastic Agents Applications Grants Autophagocytosis Autophagolysosome Autophagosome Biological Factors Biological Markers Cancer Control Research Categories Cell Death Cell Survival Cells Ceramides Chemoprevention Chemopreventive Agent Clinical Complex Dietary Factors Enzyme Inhibition Enzymes Evaluation Fenretinide Follow-Up Studies Goals Grant Hydrolysis In Vitro Individual Intervention Investigation Laboratories Lesion Light Link Liquid Chromatography MCF7 cell Malignant Neoplasms Mediator of activation protein Metabolic Metabolic stress Metabolism Methods Monitor Nutrient Outcome Pathway interactions Pharmaceutical Preparations Phosphorylation Premalignant Prevention Research Production Regulation Research Resveratrol Role Small Interfering RNA Sphingolipids Sphingosine Testing Time Western Blotting base cancer cell cancer chemoprevention cancer prevention cell killing cell type chemotherapeutic agent chemotherapy cytotoxic cytotoxicity dihydroceramide dihydroceramide desaturase dihydrosphingosine 1-phosphate functional outcomes galactosylgalactosylglucosylceramidase inhibitor/antagonist inorganic phosphate insight killings lipid mediator neoplastic cell prevent programs sphinganine sphingosine 1-phosphate sphingosine kinase tandem mass spectrometry tool

项目摘要

DESCRIPTION (provided by applicant): Autophagy is a promising new target for cancer chemoprevention and chemotherapy because it has the potential to prevent, reverse, or retard progression of precancerous lesions as well as to kill tumor cells by "type II" or "autophagic" cell death. Inducers of autophagy that have been associated with cancer prevention and treatment include natural products such as resveratrol and synthetic compounds such as the anti- cancer drug fenretinide (4-hydroxy-phenylretinamide); nonetheless, the link between autophagy and cancer is complex because it also affords a means of survival for cancer cells during times of nutrient limitation and metabolic stress. Hence, the optimal agent, or combination of agents, would favor "lethal" versus "protective" autophagy. This grant application concerns a recently discovered mechanism for induction of autophagy that appears to control the switch between these outcomes. The mechanism involves the induction of autophagy by ceramides (Cer), dihydroceramides (DHCer), and sphingosine 1-phosphate (S1P), with the latter being a critical determinant of whether autophagy is lethal or protective. The underlying hypothesis of this research is that in the induction of autophagy, (DH)Cer are incorporated into autophagosomes and subsequently hydrolyzed (in autophagolysosomes) to sphinganine and sphingosine, which are cytotoxic unless phosphorylated by sphingosine kinase. Thus, the most effective scenario for chemoprevention and chemotherapy via autophagic cell death would be to favor the production of (DH)Cer and sphingoid bases over sphingoid base 1-phosphates. This intervention strategy will be explored using MCF7 cells that express GFP-tagged LC3 to facilitate the monitoring of autophagy, methods for "sphingolipidomic" analysis of changes in these lipid mediators, and tools that can manipulate sphingolipid metabolism as the cells are treated with two prototypic dietary and chemotherapeutic agents (resveratrol and 4HPR, respectively) as well as other compounds selected for mechanistic information they will provide. The findings of the studies could define a new concept in cancer chemoprevention and chemotherapy, and identify useful tools and biomarkers for evaluation of these and additional agents in laboratory and clinical follow- up studies.

描述（由申请人提供）：自噬是癌症化学预防和化疗的一个有前景的新靶点，因为它有可能预防、逆转或延缓癌前病变的进展，并通过“II 型”或“自噬”细胞死亡来杀死肿瘤细胞。与癌症预防和治疗相关的自噬诱导剂包括白藜芦醇等天然产物和抗癌药物芬维A胺（4-羟基苯基维A酰胺）等合成化合物；尽管如此，自噬与癌症之间的联系很复杂，因为它还为癌细胞在营养限制和代谢应激期间提供了一种生存手段。因此，最佳药物或药物组合将有利于“致命”自噬而不是“保护性”自噬。这项拨款申请涉及最近发现的一种诱导自噬的机制，该机制似乎可以控制这些结果之间的转换。该机制涉及神经酰胺 (Cer)、二氢神经酰胺 (DHCer) 和 1-磷酸鞘氨醇 (S1P) 诱导自噬，后者是自噬是致命性还是保护性的关键决定因素。这项研究的基本假设是，在诱导自噬过程中，(DH)Cer 被纳入自噬体中，随后（在自噬溶酶体中）水解为二氢鞘氨醇和鞘氨醇，除非被鞘氨醇激酶磷酸化，否则它们具有细胞毒性。因此，通过自噬性细胞死亡进行化学预防和化疗的最有效方案是有利于 (DH)Cer 和鞘氨醇碱的产生，而不是鞘氨醇碱 1-磷酸盐。将使用表达 GFP 标记的 LC3 的 MCF7 细胞来探索这种干预策略，以促进自噬的监测，对这些脂质介质的变化进行“鞘脂组学”分析的方法，以及当细胞用两种原型处理时可以操纵鞘脂代谢的工具。饮食和化疗药物（分别是白藜芦醇和 4HPR）以及根据它们将提供的机制信息而选择的其他化合物。研究结果可以定义癌症化学预防和化疗的新概念，并确定有用的工具和生物标志物，用于在实验室和临床随访研究中评估这些药物和其他药物。