JNK contributes to temozolomide resistance of stem-like glioblastoma cells via regulation of MGMT expression. 2014

Masashi Okada, and Atsushi Sato, and Keita Shibuya, and Eriko Watanabe, and Shizuka Seino, and Shuhei Suzuki, and Manabu Seino, and Yoshitaka Narita, and Soichiro Shibui, and Takamasa Kayama, and Chifumi Kitanaka
Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990-9585, Japan.

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.

UI MeSH Term Description Entries
D003606 Dacarbazine An antineoplastic agent. It has significant activity against melanomas. (from Martindale, The Extra Pharmacopoeia, 31st ed, p564) DTIC,5-(3,3-Dimethyl-1-triazeno)imidazole-4-carboxamide,Biocarbazine,DIC,DTIC-Dome,Decarbazine,Deticene,Dimethyl Imidazole Carboxamide,Dimethyl Triazeno Imidazole Carboxamide,ICDT,NSC-45388,Carboxamide, Dimethyl Imidazole,DTIC Dome,DTICDome,Imidazole Carboxamide, Dimethyl,NSC 45388,NSC45388
D005909 Glioblastoma A malignant form of astrocytoma histologically characterized by pleomorphism of cells, nuclear atypia, microhemorrhage, and necrosis. They may arise in any region of the central nervous system, with a predilection for the cerebral hemispheres, basal ganglia, and commissural pathways. Clinical presentation most frequently occurs in the fifth or sixth decade of life with focal neurologic signs or seizures. Astrocytoma, Grade IV,Giant Cell Glioblastoma,Glioblastoma Multiforme,Astrocytomas, Grade IV,Giant Cell Glioblastomas,Glioblastoma, Giant Cell,Glioblastomas,Glioblastomas, Giant Cell,Grade IV Astrocytoma,Grade IV Astrocytomas
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000077204 Temozolomide A dacarbazine derivative that is used as an alkylating antineoplastic agent for the treatment of MALIGNANT GLIOMA and MALIGNANT MELANOMA. 8-Carbamoyl-3-methylimidazo(5,1-d)-1,2,3,5-tetrazin-4(3H)-one,CCRG 81045,CCRG-81045,M&B 39831,M&B-39831,Methazolastone,NSC 362856,NSC-362856,TMZ-Bioshuttle,TMZA-HE,Temodal,Temodar,Temozolomide Hexyl Ester,CCRG81045,M&B39831,NSC362856,TMZ Bioshuttle
D000873 Anthracenes A group of compounds with three aromatic rings joined in linear arrangement.
D012333 RNA, Messenger RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm. Messenger RNA,Messenger RNA, Polyadenylated,Poly(A) Tail,Poly(A)+ RNA,Poly(A)+ mRNA,RNA, Messenger, Polyadenylated,RNA, Polyadenylated,mRNA,mRNA, Non-Polyadenylated,mRNA, Polyadenylated,Non-Polyadenylated mRNA,Poly(A) RNA,Polyadenylated mRNA,Non Polyadenylated mRNA,Polyadenylated Messenger RNA,Polyadenylated RNA,RNA, Polyadenylated Messenger,mRNA, Non Polyadenylated
D014407 Tumor Cells, Cultured Cells grown in vitro from neoplastic tissue. If they can be established as a TUMOR CELL LINE, they can be propagated in cell culture indefinitely. Cultured Tumor Cells,Neoplastic Cells, Cultured,Cultured Neoplastic Cells,Cell, Cultured Neoplastic,Cell, Cultured Tumor,Cells, Cultured Neoplastic,Cells, Cultured Tumor,Cultured Neoplastic Cell,Cultured Tumor Cell,Neoplastic Cell, Cultured,Tumor Cell, Cultured
D014410 Tumor Stem Cell Assay A cytologic technique for measuring the functional capacity of tumor stem cells by assaying their activity. It is used primarily for the in vitro testing of antineoplastic agents. Clonogenic Cell Assay, Tumor,Colony-Forming Units Assay, Tumor,Neoplasm Stem Cell Assay,Stem Cell Assay, Tumor,Colony Forming Units Assay, Tumor
D014411 Neoplastic Stem Cells Highly proliferative, self-renewing, and colony-forming stem cells which give rise to NEOPLASMS. Cancer Stem Cells,Colony-Forming Units, Neoplastic,Stem Cells, Neoplastic,Tumor Stem Cells,Neoplastic Colony-Forming Units,Tumor Initiating Cells,Cancer Stem Cell,Cell, Cancer Stem,Cell, Neoplastic Stem,Cell, Tumor Initiating,Cell, Tumor Stem,Cells, Cancer Stem,Cells, Neoplastic Stem,Cells, Tumor Initiating,Cells, Tumor Stem,Colony Forming Units, Neoplastic,Colony-Forming Unit, Neoplastic,Initiating Cell, Tumor,Initiating Cells, Tumor,Neoplastic Colony Forming Units,Neoplastic Colony-Forming Unit,Neoplastic Stem Cell,Stem Cell, Cancer,Stem Cell, Neoplastic,Stem Cell, Tumor,Stem Cells, Cancer,Stem Cells, Tumor,Tumor Initiating Cell,Tumor Stem Cell,Unit, Neoplastic Colony-Forming,Units, Neoplastic Colony-Forming
D015153 Blotting, Western Identification of proteins or peptides that have been electrophoretically separated by blot transferring from the electrophoresis gel to strips of nitrocellulose paper, followed by labeling with antibody probes. Immunoblotting, Western,Western Blotting,Western Immunoblotting,Blot, Western,Immunoblot, Western,Western Blot,Western Immunoblot,Blots, Western,Blottings, Western,Immunoblots, Western,Immunoblottings, Western,Western Blots,Western Blottings,Western Immunoblots,Western Immunoblottings

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