TRAP-1调控线粒体功能并参与乳腺癌发生发展的机制研究

Breast cancer is the most common cancer and the first leading cause of cancer death in women. Current therapies decrease mortality from breast cancer, but their efficacy is limited by intrinsic and acquired therapeutic resistance and metastasis in patients. Tumor necrosis factor-associated protein 1 (TRAP-1) is a heat shock protein in mitochondria and its high expression is a common trait in colon and prostate cancers detected in primary tumor samples. TRAP-1 may contribute to the tumor progression, relapse and development of drug resistance. Our preliminary data revealed that high-expression of TRAP-1 can be found in tumors derived from breast cancer patients. It implies that TRAP-1 can be up-regulated during tumor formation. Furthermore, we found that TRAP-1 controls mitochondrial morphology change and could act as the regulator of mitochondrial dynamics. Notably, over-expression of TRAP-1 in breast cancer cells enhances oxygen consumption capability, increases mitochondria membrane potentials and contributes to resistance of apoptosis induction, potentially showing that TRAP-1 contributes to enhancement of mitochondrial bioenergetic and anti-apoptosis function. Therefore, we propose to decipher the roles of TRAP-1 in breast cancer by 1) elucidating how TRAP-1 controls mitochondrial dynamics and regulates mitochondrial function in tumor cells; 2) defining the roles of TRAP-1 in the regulation of proliferation, cell cycle progression, colony formation and drug resistance in tumor cells; 3) identifying the new factor(s) regulating drug resistance through TRAP-1 pathway.Taken together, the results of these studies should have profound implications for the TRAP-1 in tumor progression, metastasis, drug resistance and therapeutic interventions of breast cancer.

乳腺癌是女性发病率和死亡率第一位的癌症，其复发、转移和耐药严重威胁患者生命。肿瘤坏死因子受体相关蛋白1（TRAP-1）定位于线粒体，可能在前列腺癌、结肠癌发生、复发和耐药中起重要作用。申请人初步发现在乳腺癌病人标本中TRAP-1高表达，而在相应的癌旁组织中低表达；在乳腺癌细胞中过表达TRAP-1可以明显改变线粒体分裂/融合的动态平衡，显著提升细胞的（极限）有氧呼吸速率、提高线粒体膜电势，并增强细胞对凋亡诱导因素的抵抗能力，提示TRAP-1可调控线粒体功能并影响细胞命运。本申请拟在此基础上，①揭示TRAP-1调控乳腺癌细胞线粒体融合/分裂动态平衡及线粒体功能的分子机理；②研究TRAP-1对乳腺癌细胞增殖、细胞周期、克隆形成及耐药性的影响；③阐明TRAP-1影响药物耐受的作用机制。通过以上研究，深入探讨TRAP-1在乳腺癌发生、发展、转移和耐药中的分子作用机制，为乳腺癌的治疗提供研究基础。

线粒体是生物能量、生物合成和信号传导的重要细胞器，并处于动态变化中以适应环境的改变。肿瘤发生发展过程中，肿瘤细胞本身和/或肿瘤微环境的改变常常和线粒体重塑相关，某些条件下，线粒体重塑直接导致肿瘤发生发展。线粒体重塑包括能量合成改变、线粒体质量改变、融合分裂、细胞死亡易感性、氧化还原调控、细胞代谢调控，以及信号转导。本项目中，我们研究了①线粒体重要热休克蛋白--肿瘤坏死因子受体相关蛋白1（TRAP1），在乳腺癌发生、复发和耐药中的重要作用。发现在乳腺癌病人标本中TRAP1高表达，而在相应的癌旁组织中低表达；敲低TRAP1表达水平抑制肿瘤生长能力，增加肿瘤细胞对药物敏感性，并改变线粒体分裂融合状态以及有氧呼吸速率。通过以上研究，发现TRAP1在乳腺癌发生、发展、转移和耐药中的分子作用机制，为乳腺癌的治疗提供研究基础；② 黄腐酚是啤酒花中的黄酮类提取物，具有抗炎抗肿瘤活性。我们发现黄腐酚能够抑制肿瘤细胞线粒体复合物I活性，进而抑制细胞有氧呼吸速率和线粒体膜电势，诱发过量活性氧产生，最终引起肿瘤细胞凋亡。因此，黄腐酚对细胞能量代谢调控机制研究为黄腐酚的潜在治疗作用提供了研究基础；③维生素E类似物能够靶向肿瘤细胞线粒体，具有抗肿瘤作用。我们发现维生素E衍生物ESeroS-GS通过降低线粒体和糖酵解过程相关催化酶类，降低肿瘤细胞有氧呼吸和糖酵解速率，抑制细胞骨架组装，进而抑制肿瘤细胞迁移和侵袭，表明ESeroS-GS具有抗肿瘤作用。以上研究结果表明，靶向肿瘤细胞线粒体是治疗癌症的重要策略之一，通过对癌基因TRAP1以及小分子化合物的研究，揭示了其抗肿瘤的重用分子机理，为潜在治疗方案提供了科研线索。