title: Inhibition of JNK potentiates temozolomide-induced cytotoxicity in U87MG glioblastoma cells via suppression of Akt phosphorylation.
abstract: Glioblastoma (formally glioblastoma multiforme, GBM) represents both the most common and most malignant variant among numerous of primary brain tumors. Temozolomide (TMZ) has been used for the treatment of glioblastoma. However, less than 1/3 of glioblastomas respond to TMZ-based therapies. Therefore, strategies to enhance the effect of TMZ are needed for more effective targeted therapeutics. Stress-activated protein kinases (SAPKs) JNK and p38 MAPK have been known to have apoptotic or anti-apoptotic effects depending on cell type and condition. On the other hand, Akt is a key regulator of cellular survival and has direct effects on the apoptosis machinery. In addition, it was discovered that Akt activation is primed by the activity of JNK. We, therefore, examined whether inhibition of JNK or p38 potentiates TMZ-induced apoptosis in U87MG cells via inhibition of Akt activation. TMZ significantly induced Akt activation as well as JNK or p38 activation. Inhibition of JNK suppressed Akt activation and potentiated TMZ-induced cytotoxicity. The phosphorylation of GSK-3β and Bad, the downstream mediators of Akt, was also suppressed by the inhibition of JNK. The present data strongly suggest that there may be a crosstalk between JNK pathway and Akt pathway in glioblastoma and that further investigation based on the present data may provide a valuable approach for enhancing TMZ-induced cytotoxicity in glioblastoma.
authors.affiliation: Department of Pharmacology, School of Medicine, Kangwon National University, Chuncheon, Kangwon, Republic of Korea.
authors.forename: Van Anh
authors.initials: VA
authors.lastname: Vo
authors.affiliation: Department of Pharmacology, School of Medicine, Kangwon National University, Chuncheon, Kangwon, Republic of Korea.
authors.forename: Jae-Won
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, School of Medicine, Kangwon National University, Chuncheon, Kangwon, Republic of Korea.
authors.forename: Hee Jae
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, School of Medicine, Kangwon National University, Chuncheon, Kangwon, Republic of Korea.
authors.forename: Wanjoo
authors.initials: W
authors.lastname: Chun
authors.affiliation: Department of Anesthesiology and Pain Medicine, College of Medicine, Hallym University, Chuncheon, Republic of Korea.
authors.forename: So Young
authors.initials: SY
authors.lastname: Lim
authors.affiliation: Department of Pharmacology, School of Medicine, Kangwon National University, Chuncheon, Kangwon, Republic of Korea ksslsy@kangwon.ac.kr.
authors.forename: Sung-Soo
authors.initials: SS
authors.lastname: Kim
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D005909:Glioblastoma / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000077204:Temozolomide; D051025:bcl-Associated Death Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; D047428:Protein Kinase Inhibitors; D051025:bcl-Associated Death Protein; D003606:Dacarbazine; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D000077204:Temozolomide
keywords: Akt; JNK; Temozolomide; cytotoxicity; glioblastoma; p38