title: JNK suppression of chemotherapeutic agents-induced ROS confers chemoresistance on pancreatic cancer stem cells.
abstract: Chemoresistance associated with cancer stem cells (CSCs), which is now being held responsible for the pervasive therapy resistance of pancreatic cancer, poses a major challenge to the successful management of this devastating malignancy. However, the molecular mechanism underlying the marked chemoresistance of pancreatic CSCs remains largely unknown. Here we show that JNK, which is upregulated in pancreatic CSCs and contributes to their maintenance, is critically involved in the resistance of pancreatic CSCs to 5-fluorouracil (5-FU) and gemcitabine (GEM). We found that JNK inhibition effectively sensitizes otherwise chemoresistant pancreatic CSCs to 5-FU and GEM. Significantly, JNK inhibition promoted 5-FU- and GEM-induced increase in intracellular reactive oxygen species (ROS), and scavenging intracellular ROS by use of N-acetylcysteine impaired JNK inhibition-mediated promotion of the cytotoxicity of 5-FU and GEM. Our findings thus suggest that JNK may contribute to the chemoresistance of pancreatic CSCs through prevention of chemotherapeutic agents-induced increase in intracellular ROS. Our findings also suggest that JNK inhibition combined with 5-FU- and/or GEM-based regimens may be a rational therapeutic approach to effectively eliminate pancreatic CSCs.
authors.affiliation: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990-9585, Japan. Department of Clinical Oncology, Yamagata University School of Medicine, Yamagata 990-9585, Japan. Department of Regional Cancer Network, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Okada
authors.affiliation: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990-9585, Japan. Oncology Research Center, Research Institute for Advanced Molecular Epidemiology, Yamagata University, Yamagata 990-9585, Japan. Global COE program for Medical Sciences, Japan Society for Promotion of Science, Tokyo 102-8471, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Shibuya
authors.affiliation: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990-9585, Japan. Department of Obstetrics and Gynecology, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Seino
authors.affiliation: Department of Neurosurgery, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sato
authors.affiliation: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990-9585, Japan. Department of Clinical Oncology, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takeda
authors.affiliation: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990-9585, Japan. Oncology Research Center, Research Institute for Advanced Molecular Epidemiology, Yamagata University, Yamagata 990-9585, Japan. Global COE program for Medical Sciences, Japan Society for Promotion of Science, Tokyo 102-8471, Japan. Research Institute for Promotion of Medical Sciences, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
authors.forename: Shizuka
authors.initials: S
authors.lastname: Seino
authors.affiliation: Department of Clinical Oncology, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshioka
authors.affiliation: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990-9585, Japan. Oncology Research Center, Research Institute for Advanced Molecular Epidemiology, Yamagata University, Yamagata 990-9585, Japan. Global COE program for Medical Sciences, Japan Society for Promotion of Science, Tokyo 102-8471, Japan. Research Institute for Promotion of Medical Sciences, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
authors.forename: Chifumi
authors.initials: C
authors.lastname: Kitanaka
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000473:pathology*; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014162:Transfection; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D003841:Deoxycytidine; D048670:MAP Kinase Kinase 4; D005472:Fluorouracil; D000093542:Gemcitabine