title: IDH1 overexpression induced chemotherapy resistance and IDH1 mutation enhanced chemotherapy sensitivity in Glioma cells in vitro and in vivo.
abstract: Isocitrate dehydrogenase (IDH) is of great importance in cell metabolism and energy conversion. IDH mutation in glioma cells is reported to be associated with an increased overall survival. However, effects biological behavior of therapy of gliomas are unclear. Here, we investigated the influence of wild-type and mutated IDH genes on glioma cell biological behavior and response to chemotherapy. Relevant mechanisms were further explored. We designed our study on the background of the IDHR132H mutation. Stable cell lines were constructed by transfection. The CCK-8 method was used to assess cell proliferation, flow cytometry for the cell cycle and cell apoptosis, and the transwell method for cell invasion. Nude mouse models were employed to determine tumorigenesis and sensitivity to chemotherapy. Western blotting was used to detect relevant protein expression levels. We found that overexpression of wild IDH1 gene did not cause changes in the cell cycle, apoptosis and invasion ability. However, it resulted in chemotherapy resistance to a high dose of temozolomide (TMZ) in vivo and in vitro. The IDH1 mutation caused cell cycle arrest in G1 stage and a reduction of proliferation and invasion ability, while raising sensitivity to chemotherapy. This may provide an explanation for the better prognosis of IDH1 mutated glioma patients and the relative worse prognosis of their wild-type IDH1 counterparts. We also expect IDH1 mutations may be optimized as new targets to improve the prognosis of glioma patients.
authors: Department of Neurosurgery, First Affiliated Hospital of Medical College, Xi'An Jiao-tong University, Xi'An, China E-mail : 5195861@qq.com.
authors: Ju-Bo
authors: JB
authors: Wang
authors: Dan-Feng
authors: DF
authors: Dong
authors: Mao-De
authors: MD
authors: Wang
authors: Ke
authors: K
authors: Gao
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics; D015870:Gene Expression; D005910:Glioma / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D000077204:Temozolomide
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D000077204:Temozolomide