title: Autophagy promotes paclitaxel resistance of cervical cancer cells: involvement of Warburg effect activated hypoxia-induced factor 1-α-mediated signaling.
abstract: Paclitaxel is one of the most effective chemotherapy drugs for advanced cervical cancer. However, acquired resistance of paclitaxel represents a major barrier to successful anticancer treatment. In this study, paclitaxel-resistant HeLa sublines (HeLa-R cell lines) were established by continuous exposure and increased autophagy level was observed in HeLa-R cells. 3-Methyladenine or ATG7 siRNA, autophagy inhibitors, could restore sensitivity of HeLa-R cells to paclitaxel compared with parental HeLa cells. To determine the underlying molecular mechanism, differentially expressed proteins between HeLa and HeLa-R cells were identified by two-dimensional gel electrophoresis coupled with electrospray ionization quadrupole time-of-flight MS/MS. We found glycolysis-associated proteins were upregulated in HeLa-R cell lines. Inhibition of glycolysis by 2-deoxy-D-glucose or koningic acid could decrease autophagy and enhance sensitivity of HeLa-R cells to paclitaxel. Moreover, glycolysis could activate HIF1-α. Downregulation of HIF1-α by specific siRNA could decrease autophagy and resensitize HeLa-R cells to paclitaxel. Taken together, a possible Warburg effect activated HIF1-α-mediated signaling-induced autophagic pathway is proposed, which may provide new insight into paclitaxel chemoresistance.
authors.affiliation: Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: X
authors.initials: X
authors.lastname: Peng
authors.affiliation: Department of Gynecology and Obstetrics, Second West China Hospital; and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: F
authors.initials: F
authors.lastname: Gong
authors.affiliation: Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: M
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: S
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: M
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Pathology, Zunyi Medical College, Zunyi 563003, People's Republic of China.
authors.forename: G
authors.initials: G
authors.lastname: Xiao
authors.affiliation: Department of Pathology, Wenzhou Central Hospital, Wenzhou 325000, People's Republic of China.
authors.forename: H
authors.initials: H
authors.lastname: Liao
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D001343:Autophagy / Q000187:drug effects*; D000071193:Autophagy-Related Protein 7; D003847:Deoxyglucose / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D006019:Glycolysis / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D017239:Paclitaxel / Q000633:toxicity*; D034622:RNA Interference; D012717:Sesquiterpenes / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D044764:Ubiquitin-Activating Enzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D012717:Sesquiterpenes; C025946:3-methyladenine; C027285:heptelidic acid; D003847:Deoxyglucose; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes; D000225:Adenine; D017239:Paclitaxel