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IDH1 R132H mutation regulates glioma chemosensitivity through Nrf2 pathway

Kaishu Li1,2,3, Leping Ouyang1, Mingliang He1,2

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

Oncotarget
|April 22, 2017
PubMed
Abstract

Insights

The isocitrate dehydrogenase 1 (IDH1) R132H mutation increases glioma sensitivity to temozolomide by decreasing nuclear factor-erythroid 2-related factor 2 (Nrf2) expression, revealing a key mechanism for drug resistance.

Area of Science:

  • Neuro-oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Glioma patients with IDH1 R132H mutations often show temozolomide sensitivity.
  • The precise mechanism underlying IDH1 mutations' impact on glioma chemosensitivity is not fully understood.

Purpose of the Study:

  • To investigate the role of nuclear factor-erythroid 2-related factor 2 (Nrf2) in IDH1 R132H-mediated drug resistance in glioma.
  • To elucidate the potential molecular mechanisms involved.

Main Methods:

  • Generated stable U87 and U251 cell lines overexpressing wild-type IDH1 (IDH1-WT) and mutant IDH1 (IDH1 R132H).
  • Assessed phenotypic differences using MTT assays, colony formation assays, scratch tests, and flow cytometry.
  • Analyzed the expression of IDH1, Nrf2, NAD(P)H quinine oxidoreductase 1 (NQO1), multidrug resistant protein 1 (MRP1), and p53.

Main Results:

  • IDH1 R132H overexpressing cells demonstrated increased sensitivity to temozolomide compared to IDH1-WT cells.
  • Nrf2 expression and nuclear translocation were significantly decreased in IDH1 R132H cells, particularly after temozolomide treatment.
  • Knocking down Nrf2 reduced temozolomide resistance, and reduced NQO1 expression was observed in IDH1 R132H cells, with p53 involvement noted.

Conclusions:

  • Nrf2 plays a critical role in IDH1 R132H-mediated temozolomide resistance in glioma.
  • This study offers novel insights into glioma chemotherapy strategies involving temozolomide.
Keywords:
IDH1NQO1Nrf2chemotherapytemozolomide

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