Mutant IDH1 Enhances Temozolomide Sensitivity via Regulation of the ATM/CHK2 Pathway in Glioma

Lin Lin; Jinquan Cai; Zixiao Tan; Xiangqi Meng; Ruiyan Li; Yang Li; Chuanlu Jiang

추천

검색

자료유형: 학술저널

저자정보: Lin Lin (Second Affiliated Hospital of Harbin Medical University Harbin China) Jinquan Cai (Second Affiliated Hospital of Harbin Medical University Harbin China) Zixiao Tan (Second Affiliated Hospital of Harbin Medical University Harbin China) Xiangqi Meng (Second Affiliated Hospital of Harbin Medical University Harbin China) Ruiyan Li (Second Affiliated Hospital of Harbin Medical University Harbin China) Yang Li (Second Affiliated Hospital of Harbin Medical University Harbin China) Chuanlu Jiang (Second Affiliated Hospital of Harbin Medical University Harbin China)

저널정보: 대한암학회 Cancer Research and Treatment Cancer Research and Treatment 제53권 제2호

발행연도: 2021.1

수록면: 367 - 377 (11page)

이용수

📌

연구주제

📖

연구배경

🔬

연구방법

🏆

연구결과

초록· 키워드

오류제보하기

Purpose Isocitrate dehydrogenase 1 (IDH1) mutations are the most common genetic abnormalities in low-grade gliomas and secondary glioblastomas. Glioma patients with these mutations had better clinical outcomes. However, the effect of IDH1 mutation on drug sensitivity is still under debate. Materials and MethodsIDH1-R132H mutant cells were established by lentivirus. IDH1-R132H protein expression was confirmed by western blot. The expression of ataxia telangiectasia mutated (ATM) signaling pathway and apoptosis-related proteins were detected by immunofluorescence and western blot. Temozolomide (TMZ) induced cell apoptosis was detected by flow cytometry. Tumor cell proliferation was detected by Cell Counting Kit-8. In vivo nude mice were used to confirm the in vitro roles of IDH1 mutation.ResultsWe established glioma cell lines that expressed IDH1-R132H mutation stably. We found that TMZ inhibited glioma cells proliferation more significantly in IDH1 mutant cells compared to wild type. The IC50 of TMZ in IDH1-R132H mutant group was less than half that of wild-type group (p < 0.01). TMZ significantly induced more DNA damage (quantification of γH2AX expression in IDH1 mutation vs. wild type, p < 0.05) and apoptosis (quantification of AnnexinV+propidium iodide?cells in IDH1 mutation versus wild type, p < 0.01) in IDH1 mutant gliomas compared to wild-type gliomas. The ATM-associated DNA repair signal was impaired in IDH1 mutant cells. Inhibiting the ATM/checkpoint kinase 2DNA repair pathway further sensitized IDH1 mutant glioma cells to chemotherapy. We found that IDH1 mutation significantly inhibited tumor growth in vivo (the tumor size was analyzed statistically, p < 0.05). Moreover, we confirmed that gliomas with IDH1 mutation were more sensitive to TMZ in vivo compared to wild type significantly and the results were consistent with the in vitro experiment. ConclusionThese results provide evidence that combination of TMZ and ATM inhibitor enhances the antitumor effect in IDH1 mutant gliomas.

#Isocitrate dehydrogenase 1 #Temozolomide #Glioma #Ataxia telangiectasia mutated

참고문헌 (26)

참고문헌 신청

Louis DN / 2016 / The 2016 World Health Organization classification of tumors of the central nervous system : a summary / Acta Neuropathol 131:803~820

Stupp R / 2005 / Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma / N Engl J Med 352:987~996

Stupp R / 2001 / Current and future developments in the use of temozolomide for the treatment of brain tumours / Lancet Oncol 2:552~560

Dang L / 2009 / Cancer-associated IDH1 mutations produce 2-hydroxyglutarate / Nature 462:739~744

2017 / 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity / Sci Transl Med 9:eaal2463

함께 읽어보면 좋을 논문

논문 유사도에 따라 DBpia 가 추천하는 논문입니다. 함께 보면 좋을 연관 논문을 확인해보세요!