title: Akt and β-catenin contribute to TMZ resistance and EMT of MGMT negative malignant glioma cell line.
abstract: Glioblastoma is one of the most lethal cancers in central nervous system, and some individual cells that cannot be isolated for surgical resection and also show treatment-resistance induce poor prognosis. Hence, in order to research these cells, we treated temozolomide (TMZ)-sensitive U87MG cells with 400μM TMZ in culture media for over 6months and established TMZ-resistant cell line designated as U87/TR. We detected the MGMT status through pyrosequencing and western blotting, and we also assessed the proliferation, migration, EMT-like changes and possible activated signaling pathways in U87/TR cells. Our results demonstrated that U87/TR was MGMT negative, which indicated that MGMT made no contribution for TMZ-resistance of U87/TR. And U87/TR cells displayed cell cycle arrest, higher capacity for migration and EMT-like changes including both phenotype and characteristic proteins. We also revealed that both β-catenin and the phosphorylation level of Akt and PRAS40 were increased in U87/TR, while we did not observe the phosphorylation of mTOR in U87/TR. It indicated that activation of Akt and Wnt/β-catenin pathways may be response for the chemo-resistance and increased invasion of U87/TR cells, and the phosphorylation of PRAS40 and inactivated mTOR may be related to cell cycle arrest in U87/TR cells.
authors.affiliation: Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Guo-Zhong
authors.initials: GZ
authors.lastname: Yi
authors.affiliation: Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; The Laboratory of Precision Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Ya-Wei
authors.initials: YW
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiang
authors.affiliation: Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Hai
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Zi-Yang
authors.initials: ZY
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Si-di
authors.initials: SD
authors.lastname: Xie
authors.affiliation: Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; The Laboratory of Precision Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Nanfang Glioma Center, Guangzhou 510515, China. Electronic address: qisongtaonfyy@126.com.
authors.forename: Song-Tao
authors.initials: ST
authors.lastname: Qi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000235:genetics; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C484523:AKT1S1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D018906:Antineoplastic Agents, Alkylating; C495270:CTNNB1 protein, human; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D045643:DNA Repair Enzymes; D000077204:Temozolomide
keywords: Akt; Epithelial-to-mesenchymal transition; Gliomas; MGMT; Temozolomide resistance; β-catenin