title: Pivotal role for ROS activation of p38 MAPK in the control of differentiation and tumor-initiating capacity of glioma-initiating cells.
abstract: Reactive oxygen species (ROS) are involved in various aspects of cancer cell biology, yet their role in cancer stem cells (CSCs) has been poorly understood. In particular, it still remains unclear whether and how ROS control the self-renewal/differentiation process and the tumor-initiating capacity of CSCs. Here we show that ROS-mediated activation of p38 MAPK plays a pivotal role in the control of differentiation and tumor-initiating capacity of glioma-initiating cells (GICs) derived from human glioblastomas. Mechanistically, ROS triggered p38-dependent Bmi1 protein degradation and FoxO3 activation in GICs, which were shown to be responsible for the loss of their self-renewal capacity and differentiation, respectively. Thus, the results suggest that Bmi1 and FoxO3 govern distinct phases of transition from undifferentiated to fully differentiated cells. Furthermore, we also demonstrate in this study that oxidative stress deprives GICs of their tumor-initiating capacity through the activation of the ROS-p38 axis. As such, this is the first study to the best of our knowledge to delineate how ROS control self-renewal/differentiation and the tumor-initiating capacity of stem-like cancer cells. This study also suggests that targeting of the ROS-p38 axis could be a novel approach in the development of therapeutic strategies against gliomas, represented by glioblastoma.
authors.affiliation: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990-9585, Japan; Department of Neurosurgery, Yamagata University School of Medicine, Yamagata 990-9585, Japan. Electronic address: asato@med.id.yamagata-u.ac.jp.
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.
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 the 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; Oncology Research Center, Research Institute for Advanced Molecular Epidemiology, Yamagata University, Yamagata 990-9585, Japan; Global COE Program for Medical Sciences, Japan Society for the Promotion of Science, Tokyo 102-8471, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Watanabe
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 the Promotion of Science, Tokyo 102-8471, Japan.
authors.forename: Shizuka
authors.initials: S
authors.lastname: Seino
authors.affiliation: Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Narita
authors.affiliation: Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Shibui
authors.affiliation: Department of Neurosurgery, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
authors.forename: Takamasa
authors.initials: T
authors.lastname: Kayama
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 the Promotion of Science, Tokyo 102-8471, Japan. Electronic address: ckitanak@med.id.yamagata-u.ac.jp.
authors.forename: Chifumi
authors.initials: C
authors.lastname: Kitanaka
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005910:Glioma / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000637:transplantation; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014183:Transplantation, Heterologous; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D007093:Imidazoles; D011725:Pyridines; D017382:Reactive Oxygen Species; D019328:Buthionine Sulfoximine; D006861:Hydrogen Peroxide; C481581:MAPK7 protein, human; D048054:Mitogen-Activated Protein Kinase 7; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; D000111:Acetylcysteine
keywords: 2′,7′-dichlorofluorescein diacetate; BSO; CSC; DCF-DA; GFAP; GIC; GSH; N-acetylcysteine; NAC; ROS; cancer stem cell; glial fibrillary acidic protein; glioma-initiating cell; glutathione; l-buthionine-sulfoximine; reactive oxygen species