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由TACO1线粒体转移驱动的增强氧化酸化促进了膀癌中的干细胞和 Cisplatin 耐药性

Minhua Deng^1,2, Zhaohui Zhou^1,2, Jiawei Chen^1,2,3

¹State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.

Advanced science (Weinheim, Baden-Wurttemberg, Germany)

|December 10, 2024

概括

线粒体TACO1通过增强OXPHOS和mtROS,促进膀癌干细胞和西斯普拉丁耐药性. 针对这种途径可以克服化学抵抗,并预测治疗反应.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
生物化学生物化学

背景情况:

化学抵抗是膀癌 (BCa) 治疗的一个主要挑战.
氧化酸化 (OXPHOS) 的升高与癌症干和化学抵抗有关.
驱动化学耐药癌细胞中OXPHOS增加的机制尚未完全理解.

研究的目的:

为了研究 mitochondrial转化激活器的作用细胞氧化酶子单元1 (TACO1) 在BCa干和抗西斯普拉丁耐药性.
为了阐明将TACO1,OXPHOS和BCa.中的化学抵抗联系在一起的分子机制.
确定TACO1作为潜在的治疗标和预测生物标志物.

主要方法:

研究了BCa细胞中TACO1表达,干性和西斯普拉丁耐药性之间的关联.
分析了TACO1在调节线粒体细胞染色体c氧化酶I (MTCO1) 翻译和OXPHOS中的作用.
研究了热冲击蛋白90β (HSP90β) 和circFOXK2在TACO1线粒体转移中的参与.
评估了TACO1-circFOXK2-HSP90β复合物的突变对BCa细胞行为的影响.
相关联的线粒体TACO1表达与BCa患者的思普拉丁治疗反应.

主要成果:

线粒体TACO1表达与BCa.a.中的茎性和西斯普拉丁耐药性相关.
TACO1增强MTCO1的翻译,对OXPHOS和线粒体ROS (mtROS) 进行上调,从而促进干性和耐药性.
HSP90β调解了TACO1的线粒体转移,circFOXK2作为TACO1-HSP90β相互作用的支架.
破坏TACO1-circFOXK2-HSP90β复合体的突变通过抑制MTCO1/OXPHOS/mtROS轴来抑制干性和西斯普拉丁耐药性.
在BCa患者中线粒体TACO1表达的增加预示着对西斯的反应不佳.

结论:

TACO1是通过MTCO1/OXPHOS/mtROS通路的BCa干和 Cisplatin 耐药性的关键驱动因素.
TACO1-HSP90β-circFOXK2复合体对于TACO1在促进化学抵抗方面的功能至关重要.
针对TACO1或其调节复合体提供了一种潜在的策略,以克服BCa中西斯普拉丁耐药性.
线粒体TACO1作为一个有价值的生物标志物,用于预测BCa患者的西斯普拉丁治疗结果.

关键词:

在 TACO1 中.膀癌:膀癌是一种癌症.癌症的茎性癌症的茎性化学电阻是一种化学电阻.氧化酸化是一种氧化酸化.

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