1. Academic Validation
  2. CAB39 promotes cisplatin resistance in bladder cancer via the LKB1-AMPK-LC3 pathway

CAB39 promotes cisplatin resistance in bladder cancer via the LKB1-AMPK-LC3 pathway

  • Free Radic Biol Med. 2023 Sep 17;S0891-5849(23)00641-X. doi: 10.1016/j.freeradbiomed.2023.09.017.
Dongyang Gao 1 Runchang Wang 1 Yuwen Gong 1 Xiaoquan Yu 2 Niu Qian 3 Enguang Yang 1 Guangrui Fan 1 Junhai Ma 4 Chaohu Chen 1 Yan Tao 1 Jianzhong Lu 1 Zhiping Wang 5
Affiliations

Affiliations

  • 1 Institute of Urology, Lanzhou University Second Hospital, Key Laboratory of Urological Diseases in Gansu Province, Gansu Nephro-Urological Clinical Center, Lanzhou, Gansu, 730030, China.
  • 2 Ministry of Education Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, 730000, China.
  • 3 Department of Pathology, Lanzhou University Second Hospital, Lanzhou, China.
  • 4 Department of Urology, Lanzhou University Second Hospital, Lanzhou, China.
  • 5 Institute of Urology, Lanzhou University Second Hospital, Key Laboratory of Urological Diseases in Gansu Province, Gansu Nephro-Urological Clinical Center, Lanzhou, Gansu, 730030, China. Electronic address: wangzplzu@163.com.
Abstract

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.

Keywords

Autophagy; Bladder cancer; CAB39; Chloroquine; Cisplatin resistance; Reactive oxygen species.

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