title: Autophagic flux promotes cisplatin resistance in human ovarian carcinoma cells through ATP-mediated lysosomal function.
abstract: Lysosomes are involved in promoting resistance of cancer cells to chemotherapeutic agents. However, the mechanisms underlying lysosomal influence of cisplatin resistance in ovarian cancer remain incompletely understood. We report that, compared with cisplatin-sensitive SKOV3 cells, autophagy increases in cisplatin-resistant SKOV3/DDP cells treated with cisplatin. Inhibition of early-stage autophagy enhanced cisplatin-mediated cytotoxicity in SKOV3/DDP cells, but autophagy inhibition at a later stage by disturbing autophagosome-lysosome fusion is more effective. Notably, SKOV3/DDP cells contained more lysosomes than cisplatin-sensitive SKOV3 cells. Abundant lysosomes and lysosomal cathepsin D activity were required for continued autolysosomal degradation and maintenance of autophagic flux in SKOV3/DDP cells. Furthermore, SKOV3/DDP cells contain abundant lysosomal ATP required for lysosomal function, and inhibition of lysosomal ATP accumulation impaired lysosomal function and blocked autophagic flux. Therefore, our findings suggest that lysosomes at least partially contribute to cisplatin resistance in ovarian cancer cells through their role in cisplatin-induced autophagic processes, and provide insight into the mechanism of cisplatin resistance in tumors.
authors.affiliation: Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Liwei
authors.initials: L
authors.lastname: Ma
authors.affiliation: Medical Research Lab, Jilin Medical University, Changchun, Jilin 132013, P.R. China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Su
authors.affiliation: Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Huimei
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Kang
authors.affiliation: Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Xie
authors.affiliation: Department of Pathology, Basic Medical College, BeiHua University, Changchun, Jilin 132013, P.R. China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Liankun
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000255:Adenosine Triphosphate; D002945:Cisplatin