IDH1 R132H mutation regulates glioma chemosensitivity through Nrf2 pathway

Kaishu Li; Leping Ouyang; Mingliang He; Ming Luo; Wangqing Cai; Yalin Tu; Rongbiao Pi; Anmin Liu

doi:10.18632/oncotarget.15868

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Research Papers:

IDH1 R132H mutation regulates glioma chemosensitivity through Nrf2 pathway

Kaishu Li, Leping Ouyang, Mingliang He, Ming Luo, Wangqing Cai, Yalin Tu, Rongbiao Pi and Anmin Liu _

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Oncotarget. 2017; 8:28865-28879. https://doi.org/10.18632/oncotarget.15868

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Abstract

Kaishu Li1,2,5,*, Leping Ouyang1,*, Mingliang He1,2,*, Ming Luo2,3, Wangqing Cai1, Yalin Tu4, Rongbiao Pi4, Anmin Liu1,2

1Department of Neurosurgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, PR China

2Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, PR China

3Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, PR China

4Department of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510080, PR China

5Department of Neurosurgery, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan 511500, PR China

*These authors have contributed equally to this work

Correspondence to:

Anmin Liu, email: [email protected]

Ming Luo, email: [email protected]

Keywords: IDH1, Nrf2, NQO1, temozolomide, chemotherapy

Received: October 12, 2016 Accepted: February 13, 2017 Published: March 03, 2017

ABSTRACT

Purpose: Numerous studies have reported that glioma patients with isocitrate dehydrogenase 1(IDH1) R132H mutation are sensitive to temozolomide treatment. However, the mechanism of IDH1 mutations on the chemosensitivity of glioma remains unclear. In this study, we investigated the role and the potential mechanism of Nrf2 in IDH1 R132H-mediated drug resistance.

Methods: Wild type IDH1 (R132H-WT) and mutant IDH1 (R132H) plasmids were constructed. Stable U87 cells and U251 cells overexpressing IDH1 were generated. Phenotypic differences between IDH1-WT and IDH1 R132H overexpressing cells were evaluated using MTT, cell colony formation assay, scratch test assay and flow cytometry. Expression of IDH1 and its associated targets, nuclear factor-erythroid 2-related factor 2 (Nrf2), NAD(P)H quinine oxidoreductase 1 (NQO1), multidrug resistant protein 1 (MRP1) and p53 were analyzed.

Results: The IDH1 R132H overexpressing cells were more sensitive to temozolomide than WT and the control, and Nrf2 was significantly decreased in IDH1 R132H overexpressing cells. We found that knocking down Nrf2 could decrease resistance to temozolomide. The nuclear translocation of Nrf2 in IDH1 R132H overexpressing cells was lower than the WT and the control groups after temozolomide treatment. When compared with WT cells, NQO1 expression was reduced in IDH1 R132H cells, especially after temozolomide treatment. P53 was involved in the resistance mechanism of temozolomide mediated by Nrf2 and NQO1.

Conclusions: Nrf2 played an important role in IDH1 R132H-mediated drug resistance. The present study provides new insight for glioma chemotherapy with temozolomide.

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Research Papers:

IDH1 R132H mutation regulates glioma chemosensitivity through Nrf2 pathway

Abstract