Anticancer Drug Resistance by Bcl-2 Oncogene Expression

Bcl-2 癌基因表达引起的抗癌药物耐药性

• 批准号: 7069989
• 负责人: RAYMOND E MEYN
• 金额: $ 26.54万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-06-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7069989
• 关键词: BCL2 gene /protein; antineoplastics; apoptosis; biological signal transduction; cell line; cell membrane; clinical research; drug screening /evaluation; gene expression; glutathione; intracellular transport; mitochondria; mitochondrial membrane; multidrug resistance; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; oncogenes; protein localization; tissue /cell culture

DESCRIPTION (provided by applicant): The goal of this research project has been and remains to define the mechanism responsible for the resistance of tumor cells with abnormal expression of the Bcl-2 oncogene to cancer chemotherapy agents. Bcl-2 is the prototypic member of a family of proteins, whose main function appears to be the regulation of apoptosis. Bcl-2 is highly expressed in a variety of human cancers and provides a growth advantage to tumors by blocking apoptosis during tumor progression. However, this block also renders such tumor cells resistant to anticancer therapies including most cancer chemotherapy drugs that rely on apoptosis as their primary mode of cell killing. Indeed, Bcl-2 expression produces a multi-drug resistance (MDR) phenotype. The mechanism by which Bcl-2 regulates apoptosis is not understood. We have previously shown that Bcl-2 expressing cells have higher intracellular levels of glutathione (GSH). As we demonstrate in this application, the mitochondria from Bcl-2 expressing cells also have higher GSH levels and have enhanced capacity to actively transport GSH from the cytosol into mitochondria. These are novel findings that are entirely consistent with the ability of Bcl-2 to suppress mitochondrial apoptosis; it is our contention that MDR due to Bcl-2 expression could be reversed by inhibiting or reversing Bcl-2's enhancement of mitochondrial GSH levels. Therefore, in this application, Specific Aims 1 and 2 are directed at characterizing this effect of Bcl-2 on mitochondrial GSH transport and testing the hypothesis that the level of mitochondrial GSH directly regulates mitochondrial apoptosis. In Aim 3, we propose to follow up on a new lead and investigate whether Bcl-2 protein is redistributed to the plasma membrane after cells receive an apoptotic signal. Finally, we propose in Specific Aim 4 to investigate strategies for overcoming Bcl-2 mediated MDR through the use of drugs that enable GSH efflux from cells or mitochondria. The significance of this project relates to the problem of MDR in cancer therapeutics. It is our central hypothesis that understanding the biochemical and molecular basis for Bcl-2's ability to block anticancer-drug induced apoptosis will lead to the development of strategies for reversing this drug resistance and enhancing therapeutic effects.

描述（由申请人提供）：该研究项目的目的是并且仍在定义导致肿瘤细胞具有异常表达的肿瘤细胞对癌症化学疗法剂的抗性的机制。 Bcl-2是蛋白质家族的原型成员，其主要功能似乎是凋亡的调节。 Bcl-2在各种人类癌症中高度表达，并通过阻断肿瘤进展过程中的凋亡来为肿瘤提供生长优势。但是，该阻滞还使这种抗癌疗法具有抗性肿瘤细胞，包括大多数依赖凋亡作为其主要细胞杀死方式的癌症化学疗法药物。实际上，Bcl-2表达会产生多药抗性（MDR）表型。尚不了解Bcl-2调节凋亡的机制。我们以前已经表明，Bcl-2表达细胞具有较高的细胞内谷胱甘肽（GSH）。正如我们在本应用中所证明的那样，来自Bcl-2表达细胞的线粒体也具有较高的GSH水平，并且具有将GSH从胞质溶胶中运输到线粒体的能力增强。这些是与Bcl-2抑制线粒体凋亡的能力完全一致的新颖发现。我们的论点是，由于Bcl-2表达引起的MDR可以通过抑制或逆转Bcl-2的增强线粒体GSH水平来逆转。因此，在此应用中，特定的目标1和2旨在表征Bcl-2对线粒体GSH转运的影响，并检验线粒体GSH水平直接调节线粒体细胞凋亡的假设。在AIM 3中，我们建议跟进新的铅，并研究细胞收到凋亡信号后Bcl-2蛋白是否将Bcl-2蛋白重新分布在质膜。最后，我们在特定的目标4中提出，通过使用能够从细胞或线粒体的GSH外排来克服BCL-2介导的MDR的策略。该项目的意义与癌症治疗中的MDR问题有关。我们的核心假设是，了解Bcl-2阻断抗癌 - 药物诱导的凋亡能力的生化和分子基础将导致发展这种耐药性并增强治疗作用的策略。