The role of arachidonic acid in estrogen mediated mTOR activation

花生四烯酸在雌激素介导的 mTOR 激活中的作用

• 批准号: 8509187
• 负责人: YU JIANG
• 金额: $ 19.9万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8509187
• 关键词: Arachidonic Acids; Biotin; Breast; Breast Cancer Cell; Breast Cancer Treatment; Cancer Patient; Cells; Complex; DNA; Detection; Development; Drug resistance; Estrogen Receptors; Estrogen receptor positive; Estrogens; Gap Junctions; Genetic Transcription; Investigation; Label; Laboratories; Lead; Light; Link; Lipid Peroxidation; Lipids; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Membrane; Metabolic; Metabolic Pathway; Modification; Molecular; Pathway interactions; Play; Process; Production; Proteins; Regulation; Research; Research Personnel; Research Project Grants; Resistance; Role; Sampling; Scheme; Signal Transduction; Site; Testing; Therapeutic; Therapeutic Agents; angiogenesis; base; cancer type; conventional therapy; hormone therapy; human FRAP1 protein; inhibitor/antagonist; mTOR Signaling Pathway; mTOR inhibition; malignant breast neoplasm; non-genomic; novel; outcome forecast; public health relevance; stem; tumor; tumor growth

DESCRIPTION (provided by applicant): In estrogen receptor positive (ER+) breast cancer, an elevated mTOR activity causes resistance to conventional chemo- and hormonal therapies. Estrogen and its membrane- associated estrogen receptors are known to contribute to this abnormal mTOR activity independent of their role in transcription. However, the underlying mechanism remains unknown. Recently, arachidonic acid (AA) and its metabolites have been found to serve as key mediators for the non-genomic action of estrogen. In concert with this finding, we have observed a strong correlation between AA level and mTOR activity in tumor samples from breast cancer patients. These observations suggest a potential signaling nexus that links estrogen, AA and mTOR. This exploratory R21 project is proposed to delineate the molecular basis for this novel signaling scheme. Three lines of investigation are planned to test the hypothesis that estrogen activates mTOR through the AA metabolic cascade, including determining: 1) the role of AA metabolic cascade in estrogen-induced mTOR activation, 2) the metabolites of AA involved mTOR regulation, and 3) the mechanism by which the metabolites of AA activate mTOR. Successful completion of the proposed research will not only shed light on a novel signaling mechanism for mTOR activation but also allow further elevation of the therapeutic implication of this signaling mechanism in breast cancer treatment.

描述（由申请人提供）：在雌激素受体阳性（ER+）乳腺癌中，mTOR 活性升高会导致对传统化疗和激素疗法的耐药性。已知雌激素及其膜相关雌激素受体会导致这种异常的 mTOR 活性，而与它们在转录中的作用无关。然而，其根本机制仍不清楚。最近，花生四烯酸（AA）及其代谢物被发现是雌激素非基因组作用的关键介质。与这一发现相一致的是，我们观察到乳腺癌患者肿瘤样本中 AA 水平与 mTOR 活性之间存在很强的相关性。这些观察结果表明，雌激素、AA 和 mTOR 之间存在潜在的信号传导联系。提出这个探索性 R21 项目是为了描绘这种新型信号传导方案的分子基础。计划进行三方面的研究来检验雌激素通过 AA 代谢级联激活 mTOR 的假设，包括确定：1）AA 代谢级联在雌激素诱导的 mTOR 激活中的作用，2）AA 的代谢物参与 mTOR 调节，3）AA 的代谢物激活 mTOR 的机制。 该研究的成功完成不仅将揭示 mTOR 激活的新型信号机制，而且还可以进一步提高该信号机制在乳腺癌治疗中的治疗意义。