Epoxygenase Mechanisms of Breast Cancer Progression

乳腺癌进展的环氧合酶机制

• 批准号: 6903922
• 负责人: DAVID ALEXANDER POTTER
• 金额: $ 23.94万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6903922
• 关键词: athymic mouse; breast neoplasms; cell growth regulation; cell line; cytochrome P450; eicosanoid metabolism; eicosanoids; enzyme activity; enzyme induction /repression; guanine nucleotide binding protein; heat shock proteins; isomer; mass spectrometry; molecular oncology; neoplasm /cancer transplantation; neoplastic growth; neoplastic transformation; oncogenes; pharmacokinetics; ritonavir; serine threonine protein kinase; unspecific monooxygenase

DESCRIPTION (provided by applicant): Three enzymatic pathways of arachidonic acid metabolism, involving cyclooxygenases, lipoxygenases, and cytochrome P450 epoxygenases, have been identified in mammalian cells, but only the first two have been linked to human cancer. The HIV protease inhibitor, ritonavir, is a potent inhibitor of epoxygenases that arrests the growth of breast cancer xenografts, but its mechanism of action is unknown. Epoxygenases promote the production of epoxyeicosatrienoic acids (EET's) that activate Akt kinase. This project seeks to determine whether epoxygenases are cancer therapeutic targets. The hypothesis to be tested is that epoxygenase activation promotes breast cancer progression by promoting Akt phosphorylation and cancer cell survival. The specific aims are: 1. To establish the molecular mechanisms by which epoxygenases cause growth dysregulation in breast cancer, 2. To establish that epoxygenases enhance the oncogenic potential of the Ha-ras oncogene in mammary carcinoma. 3. To establish that the epoxygenase pathway activates and requires Hsp90 for cancer cell survival. Targeted lipidomics using the method of electron capture APCI-MS/MS will be used to profile EET regio- and stereoisomers. A bacterial epoxygenase will be tested for cooperation with activated Ha-ras in breast cancer progression. These studies will promote further development of epoxygenases as targets for breast cancer therapeutics.

描述（由申请人提供）：已在哺乳动物细胞中鉴定出花生四烯酸代谢的三种酶促途径，涉及环氧合酶、脂氧合酶和细胞色素P450环氧化酶，但仅前两种与人类癌症有关。 HIV蛋白酶抑制剂利托那韦是一种有效的环氧化酶抑制剂，可以阻止乳腺癌异种移植物的生长，但其作用机制尚不清楚。环氧合酶促进环氧二十碳三烯酸 (EET) 的产生，从而激活 Akt 激酶。该项目旨在确定环氧化酶是否是癌症治疗靶点。待检验的假设是环氧化酶激活通过促进 Akt 磷酸化和癌细胞存活来促进乳腺癌进展。具体目标是： 1. 确定环氧化酶引起乳腺癌生长失调的分子机制， 2. 确定环氧化酶增强乳腺癌中 Ha-ras 癌基因的致癌潜力。 3. 确定环氧化酶途径激活并需要 Hsp90 来维持癌细胞的存活。使用电子捕获 APCI-MS/MS 方法的靶向脂质组学将用于分析 EET 区域异构体和立体异构体。将测试细菌环氧化酶与激活的 Ha-ras 在乳腺癌进展中的合作。这些研究将促进环氧化酶作为乳腺癌治疗靶点的进一步发展。