肌层浸润式膀胱癌（BC）的全身治疗仍然以顺铂为基础的化疗为主导。然而，对顺铂治疗的抵抗大大限制了长期生存。仍需要解决对顺铂为基础的化疗的抵抗。在本研究中，我们通过多次顺铂脉冲处理建立了三株顺铂耐药的BC细胞系。有趣的是，在接受顺铂暴露后，所有顺铂耐药细胞系显示出比相应亲本细胞系更低的活性氧（ROS）水平。通过蛋白质组分析，我们发现35种在顺铂耐药的BC细胞中上调表达的蛋白质。通过沉默其中的11个基因，我们发现在CAB39基因沉默后，BC顺铂耐药细胞对顺铂更敏感。CAB39的过度表达则产生相反的效果。然后，通过沉默CAB39上游的6个基因，我们发现CAB39通过LKB1促进BC的顺铂抵抗。此外，顺铂诱导的细胞死亡的关键原因是对线粒体的损伤和ROS水平的增加。在我们的研究中，顺铂耐药细胞显示出更高的自噬通量和更健康的线粒体状态在接受顺铂暴露后。我们证明了CAB39-LKB1-AMPK-LC3通路在增强自噬以维持线粒体健康和降低ROS水平方面发挥关键作用。此外，自噬抑制剂氯喹（CQ）能够显著增强顺铂对BC细胞的杀伤效果。与吉西他滨加顺铂（GC）相比，GC加CQ在体内显著减少了肿瘤负担。总之，我们的研究表明，CAB39通过增强BC细胞对受损线粒体和其他细胞器的自噬而减轻细胞受有害物质如ROS所致的损伤，从而对顺铂的杀伤产生拮抗作用。版权所有©2023。Elsevier Inc.发表。

Systemic therapy for muscle-invasive bladder cancer (BC) remains dominated by cisplatin-based chemotherapy. However, resistance to cisplatin therapy greatly limits long-term survival. Resistance to cisplatin-based chemotherapy still needs to be addressed. In this study, we established three cisplatin-resistant BC cell lines by multiple cisplatin pulse treatments. Interestingly, after exposure to cisplatin, all cisplatin-resistant cell lines showed lower reactive oxygen species (ROS) levels than the corresponding parental cell lines. Using proteomic analysis, we identified 35 proteins that were upregulated in cisplatin-resistant BC cells. By knocking down eleven of these genes, we found that after CAB39 knockdown, BC cisplatin-resistant cells were more sensitive to cisplatin. Overexpression of CAB39 had the opposite effect. Then, the knockdown of six genes downstream of CAB39 revealed that CAB39 promoted cisplatin resistance in BC through LKB1. Moreover, a key cause of cisplatin-induced cell death is damage to mitochondria and increased ROS levels. In our study, cisplatin-resistant cells exhibited higher autophagic flux and healthier mitochondrial status after cisplatin exposure. We demostrated that the CAB39-LKB1-AMPK-LC3 pathway plays a critical role in enhancing autophagy to maintain the health of mitochondria and reduce ROS levels. In addition, the autophagy inhibitor chloroquine (CQ) can significantly enhance the killing effect of cisplatin on BC cells. Compared with gemcitabine plus cisplatin (GC), GC plus CQ significantly reduced tumor burden in vivo. In conclusion, our study shows that CAB39 counteracts the killing of cisplatin by enhancing the autophagy of BC cells to damaged mitochondria and other organelles to alleviate the damage of cells caused by harmful substances such as ROS.Copyright © 2023. Published by Elsevier Inc.