Deng Minhua, Zhou Zhaohui, Chen Jiawei, Li Xiangdong, Liu Zefu, Ye Jingwei, Wei Wensu, Wang Ning, Peng Yulu, Luo Xin, Jiang Lijuan, Zhou Fangjian, Zheng Xianchong, Liu Zhuowei
State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
Department of Urology, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China.
Adv Sci (Weinh). 2025 Feb;12(5):e2408599. doi: 10.1002/advs.202408599. Epub 2024 Dec 10.
Chemoresistance poses a critical obstacle in bladder cancer (BCa) treatment, and effective interventions are currently limited. Elevated oxidative phosphorylation (OXPHOS) has been linked to cancer stemness, a determinant of chemoresistance. However, the mechanisms underlying increased OXPHOS during cancer cell chemoresistance remain unclear. This study revealed that the mitochondrial translational activator of cytochrome oxidase subunit 1 (TACO1) is linked to stemness and cisplatin resistance in BCa cells. Mechanistically, mitochondrial TACO1 enhances the translation of the mitochondrial cytochrome c oxidase I (MTCO1), promoting mitochondrial reactive oxygen species (mtROS) by upregulating OXPHOS, consequently driving cancer stemness and cisplatin resistance. Intriguingly, the mitochondrial translocation of TACO1 is mediated by the heat shock protein 90 β (HSP90β), a process that requires circFOXK2 as a scaffold for the TACO1-HSP90β interaction. The mutations at the binding sites of TACO1-circFOXK2-HSP90β disturb the ternary complex and inhibit cancer stemness and cisplatin resistance in BCa cells by suppressing the MTCO1/OXPHOS/mtROS axis. Clinically, BCa patients with increased mitochondrial TACO1 expression respond poorly to cisplatin treatment. This study elucidates the mechanisms by which TACO1 promotes BCa stemness and cisplatin resistance, providing a potential target for mitigating cisplatin resistance for BCa and a biomarker for predicting cisplatin response.
化疗耐药是膀胱癌（BCa）治疗中的一个关键障碍，目前有效的干预措施有限。氧化磷酸化（OXPHOS）升高与癌症干性相关，而癌症干性是化疗耐药的一个决定因素。然而，癌细胞化疗耐药期间OXPHOS增加的潜在机制仍不清楚。本研究表明，细胞色素氧化酶亚基1的线粒体翻译激活因子（TACO1）与BCa细胞的干性和顺铂耐药相关。从机制上讲，线粒体TACO1增强线粒体细胞色素c氧化酶I（MTCO1）的翻译，通过上调OXPHOS促进线粒体活性氧（mtROS），从而驱动癌症干性和顺铂耐药。有趣的是，TACO1的线粒体易位由热休克蛋白90β（HSP90β）介导，这一过程需要circFOXK2作为TACO1-HSP90β相互作用的支架。TACO1-circFOXK2-HSP90β结合位点的突变会破坏三元复合物，并通过抑制MTCO1/OXPHOS/mtROS轴抑制BCa细胞的癌症干性和顺铂耐药。临床上，线粒体TACO1表达增加的BCa患者对顺铂治疗反应不佳。本研究阐明了TACO1促进BCa干性和顺铂耐药的机制，为减轻BCa的顺铂耐药提供了一个潜在靶点，并为预测顺铂反应提供了一个生物标志物。
