p38 MAPK-dependent Nrf2 induction enhances the resistance of glioma cells against TMZ

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 identified 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 TMZ's therapeutic efficiency.