title: JNK contributes to temozolomide resistance of stem-like glioblastoma cells via regulation of MGMT expression.
abstract: While elimination of the cancer stem cell population is increasingly recognized as a key to successful treatment of cancer, the high resistance of cancer stem cells to conventional chemoradiotherapy remains a therapeutic challenge. O6-methylguanine DNA methyltransferase (MGMT), which is frequently expressed in cancer stem cells of glioblastoma, has been implicated in their resistance to temozolomide, the first-line chemotherapeutic agent against newly diagnosed glioblastoma. However, much remains unknown about the molecular regulation that underlies MGMT expression and temozolomide resistance of glioblastoma cancer stem cells. Here, we identified JNK as a novel player in the control of MGMT expression and temozolomide resistance of glioblastoma cancer stem cells. We showed that inhibition of JNK, either pharmacologically or by RNA interference, in stem-like glioblastoma cells derived directly from glioblastoma tissues reduces their MGMT expression and temozolomide resistance. Importantly, sensitization of stem-like glioblastoma cells to temozolomide by JNK inhibition was dependent on MGMT expression, implying that JNK controls temozolomide resistance of stem-like glioblastoma cells through MGMT expression. Our findings suggest that concurrent use of JNK inhibitors with temozolomide may be a rational therapeutic approach to effectively target the cancer stem cell population in the treatment of glioblastoma.
authors: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
authors: Masashi
authors: M
authors: Okada
authors: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
authors: Atsushi
authors: A
authors: Sato
authors: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
authors: Keita
authors: K
authors: Shibuya
authors: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
authors: Eriko
authors: E
authors: Watanabe
authors: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
authors: Shizuka
authors: S
authors: Seino
authors: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
authors: Shuhei
authors: S
authors: Suzuki
authors: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
authors: Manabu
authors: M
authors: Seino
authors: Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan.
authors: Yoshitaka
authors: Y
authors: Narita
authors: Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan.
authors: Soichiro
authors: S
authors: Shibui
authors: Department of Neurosurgery, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
authors: Takamasa
authors: T
authors: Kayama
authors: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
authors: Chifumi
authors: C
authors: Kitanaka
mesh_terms: D000873:Anthracenes / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D015153:Blotting, Western; D015254:DNA Modification Methylases / Q000235:genetics / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077204:Temozolomide; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000873:Anthracenes; D018906:Antineoplastic Agents, Alkylating; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; C432165:pyrazolanthrone; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D048670:MAP Kinase Kinase 4; D045643:DNA Repair Enzymes; D000077204:Temozolomide