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.

High IDH1 expression is associated with a poor prognosis in cytogenetically normal acute myeloid leukemia

“…It is reported that cells expressing shRNAs targeting IDH1 does decrease the reprogramming of reductive glutamine carboxylation under hypoxia but not IDH2 . At the same time, over‐expression of wild‐type IDH1 displays a resistance chemotherapy phenotype . Notably, until now, most of the basic researches are still to explore the leukemogenesis of IDH mutations based on the knockin or knockout model by aberrant expression of wild‐type IDH1/2 or mutant IDH1/2 .…”

“…At the same time, over-expression of wild-type IDH1 displays a resistance chemotherapy phenotype. 18 Notably, until now, most of the basic researches are still to explore the leukemogenesis of IDH mutations based on the knockin or knockout model by aberrant expression of wild-type IDH1/2 or mutant IDH1/2. 19 This indicates that the knowledge of the native function of IDH is as important as that of mutant IDH to understand the leukemogenesis of AML patients.…”

O6-methyl-guanine-DNA methyltransferase methylation and IDH1/2 mutation in small cell lung cancer

“…The IDH mutation was associated with a higher response rate to temozolomide therapy (21). The IDH1 mutation caused cell cycle arrest at the G1 stage and a reduction of proliferation and invasion ability, while raising sensitivity to chemotherapy (22). No IDH1/2 mutations in SCLC were detected in the current study, which may be due to the limited sample quantity, as all samples were acquired from surgical specimens and only ~5% of SCLC patients with a TNM stage of T1-2N0M0 were suitable for surgery.…”

Identification of a novel metabolic-related mutation (IDH1) in metastatic pancreatic cancer

“…For instance, mutant IDH1 isoenzymes are less efficient at catalyzing the reductive carboxylation of a-ketoglutarate (into isocitrate), they are more sensitive to chemotherapy, and they are more susceptible to the ill effects of hypoxia. 1,2,29,30 Moreover, in glioblastoma multiforme, tumors with biallelic wild type IDH1 are more aggressive and associated with worse outcomes than their mutant counterparts. 1 Thus, PDA may in fact be maladapted for IDH1 mutations due to the harsh tumor microenvironment that is a hallmark of the disease.…”

“…In addition, IDH1 mutant tumors are more sensitive to both harsh metabolic conditions and chemotherapy than their wild type counterparts. 29,30 Since PDA is characterized by a harsh and nutrient deprived microenvironment (similar to primary glioblastomas which contain wild type IDH1), [31][32][33] it stands to reason that IDH1 mutations may in fact be deleterious for PDA and selected against, which could account for the absence of any reported IDH1 mutations to date. Herein, we report for the first time, a case of PDA with a bona fide and validated IDH1 R132H mutation.…”