title: Gemcitabine-induced pancreatic cancer cell death is associated with MST1/cyclophilin D mitochondrial complexation.
abstract: The pancreatic adenocarcinoma remains the most aggressive human malignancy with an extremely low 5-year overall survival. Postoperative gemcitabine could significantly delay recurrence after complete resection of pancreatic cancer. However, the underlying mechanisms are not fully understood. The chemo-resistance factors against gemcitabine still need further characterizations. Here we studied the mechanism of gemcitabine-induced pancreatic cancer cell death by focusing on mammalian sterile 20-like kinase 1 (MST1) and cyclophilin D (Cyp-D). We found that MST1 and Cyp-D expressions were significantly lower in gemcitabine-resistant pancreatic cancer tissues and cell lines. In vitro, gemcitabine activated MST1 through reactive oxygen species (ROS) production, which was prevented by antioxidant n-acetyl-cysteine (NAC). We found that gemcitabine-activated MST1 translocated to mitochondria and formed a complex with the local protein Cyp-D. Gemcitabine-induced cell death was alleviated by MST1 or Cyp-D shRNA silencing, but was aggravated by MST1 or Cyp-D over-expression. Further, cyclosporin A (CsA), the Cyp-D inhibitor, prevented gemcitabine-induced MST1/Cyp-D mitochondrial complexation and cancer cell death. We suggest that gemcitabine-induced death of pancreatic cancer cells requires MST1/Cyp-D mitochondrial complexation.
authors.affiliation: Department of Hepatobiliary Surgery, Fuzhou General Hospital of Nanjing Command, PLA, Fuzhou 350025, China.
authors.forename: Shao-Hua
authors.initials: SH
authors.lastname: Chen
authors.affiliation: Department of Hepatobiliary Medicine, Fuzhou General Hospital of Nanjing Command, PLA, Fuzhou 350025, China. Electronic address: lidongliang1970@163.com.
authors.forename: Dong-Liang
authors.initials: DL
authors.lastname: Li
authors.affiliation: Department of Hepatobiliary Surgery, Fuzhou General Hospital of Nanjing Command, PLA, Fuzhou 350025, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Yang
authors.affiliation: Department of Hepatobiliary Surgery, Fuzhou General Hospital of Nanjing Command, PLA, Fuzhou 350025, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Hepatobiliary Surgery, Fuzhou General Hospital of Nanjing Command, PLA, Fuzhou 350025, China.
authors.forename: Yong-Yang
authors.initials: YY
authors.lastname: Zhao
authors.affiliation: Department of Hepatobiliary Surgery, Fuzhou General Hospital of Nanjing Command, PLA, Fuzhou 350025, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Jiang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000235:genetics / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D010190:Pancreatic Neoplasms / Q000473:pathology*; D011487:Protein Conformation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D000093542:Gemcitabine; D000099317:Hippo Kinases
chemical_list: D000970:Antineoplastic Agents; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins; D016572:Cyclosporine; D003841:Deoxycytidine; D047908:Intracellular Signaling Peptides and Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017346:Protein Serine-Threonine Kinases; D017382:Reactive Oxygen Species; D000093542:Gemcitabine; C095566:STK4 protein, human; D000099317:Hippo Kinases
keywords: Cell death; Cyclophilin D; Gemcitabine; MST1; Pancreatic cancer