CLC3 regulates V-ATPase to enhance lysosomal degradation and cisplatin resistance in cervical cancer cells #MMPMID41339331
Chen C; Zhang F; Shen J; Zheng Q; Zhang Z; Lu S; Liu L; Zhu T; Du Y; Guan Y
Cell Death Discov 2025[Dec]; ? (?): ? PMID41339331show ga
Chemoresistance remains a major challenge in cervical cancer (CVC) treatment. Lysosomal function, mediated by V-ATPase, is critical in cancer progression and drug resistance. CLC3, a chloride channel that regulates lysosomal acidification, may contribute to chemoresistance by modulating V-ATPase activity. This study aims to investigate the role of CLC3 in modulating lysosomal function, chemoresistance, and tumorigenesis in CVC. CLC3 expression in CVC cell lines was assessed, and chemoresistance was evaluated using IC50 calculations for cisplatin, paclitaxel, and 5-FU. Effects of CLC3 downregulation or overexpression on lysosomal pH, autophagy, apoptosis, cell proliferation, cell cycle progression, and tumor stemness were analyzed. A general V-ATPase inhibitor was used to assess changes in lysosomal pH and protein degradation, while a2v-mAb was applied to investigate the interaction between CLC3 and specific V-ATPase subunits. In vivo, a mouse xenograft model was used to assess the effects of CLC3 modulation on tumor growth and response to chemoresistance. CLC3 was upregulated in CVC cells, reducing chemosensitivity. Overexpression of CLC3 enhanced cytosolic alkalinization, lysosomal acidification, and protein degradation while inhibiting autophagy and apoptosis independently. CLC3 promoted cell proliferation and tumor stemness via V-ATPase activity, particularly ATP6V1A. CLC3 knockdown combined with V-ATPase inhibition decreased proliferation and increased cisplatin sensitivity. In vivo, CLC3 knockdown with cisplatin reduced tumor volume and increased apoptosis, whereas overexpression promoted cisplatin resistance. CLC3 plays a pivotal role in chemoresistance and tumor progression in CVC by regulating lysosomal function via V-ATPase. Targeting CLC3 and its downstream pathways may provide novel therapeutic strategies to overcome chemoresistance.
Cell+Death+Discov 2025 ; ? (?): ?
