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Med Oncol (2015) 32:69DOI 10.1007/s12032-015-0517-y
ORIGINAL PAPER
p38 MAPK-dependent Nrf2 induction enhances the resistance of glioma cells against TMZ
Leina Ma Jia Liu Xinling Zhang
Jieqiong Qi Wengong Yu Yuchao Gu
Received: 30 January 2015 / Accepted: 13 February 2015 / Published online: 19 February 2015 Springer Science+Business Media New York 2015
Abstract Temozolomide (TMZ) is an effective agent for clinical glioma treatment, but the innate and acquired resistance of glioma always limits its application. Although some advances have been achieved to elucidate the molecular mechanism underlying TMZ resistance, the role of Nrf2 (a principle regulator of cellular defense against drugs and oxidative stress) has not been well established in the acquisition of this phenotype. Our data showed that TMZ treatment induces the activation of Nrf2 and p38 MAPK signaling in glioma cells, while p38 inhibition abolished the effect of TMZ on Nrf2. Further study revealed that Nrf2 silencing was able to enhance the response of glioma cells to TMZ. Additionally, Nrf2 overexpression overrides the effect of p38 MAPK activation on Temozolomide resistance. In conclusions, we identied a p38 MAPK/Nrf2 signaling as a key molecular network contributing to TMZ resistance of glioma, and provided evidence that suppressing this signaling may be a promising strategy to improve TMZs therapeutic efciency.
Keywords Temozolomide Glioma Nrf2 p38 MAPK
Introduction
Temozolomide (TMZ) has been widely applied for clinical treatment of malignant glioma. The underlying anti-tumor mechanism involves with forced methylation of DNA in target cells by the active form of TMZ, MITC (5-(3-methyl three nitrene-1-based) imidazole-4-amide). The methylation event can elicit the apoptosis in cancer cells. However, some subpopulation of glioma cells develops the resistance against the action of TMZ, thereby impairing its therapeutic efciency. The mechanism by which glioma becomes refractory to TMZ treatment has been studied for a long time. O-6-alkylguanine DNA alkyltransferase (AGT) encoded by the O-6-methylguanine-DNA methyltransferase (MGMT) gene has been reported to repair DNA damage and thus enable glioma cells insensitive to the pro-apoptotic effect of TMZ [1]. An AGT inhibitor, O-6-BG, has been shown to increase the efcacy of TMZ on glioma both in vitro and in animal models. However, mixed results from a phase-II clinical trial showed that no signicant benet from the combination of O-6-BG and TMZ on the prolonging...