De-Differentiation Confers Multidrug Resistance Via Noncanonical PERK-Nrf2 Signaling

Malignant carcinomas that recur following therapy are typically de-differentiated and multidrug resistant (mdr). de-differentiated cancer cells acquire mdr by up-regulating reactive oxygen species (ros)–scavenging enzymes and drug efflux pumps,but how these genes are up-regulated in response to de-differentiation is not known. here,we examine this question by using global transcriptional profiling to identify ros-induced genes that are already up-regulated in de-differentiated cells,even in the absence of oxidative damage. using this approach,we found that the nrf2 transcription factor,which is the master regulator of cellular responses to oxidative stress,is preactivated in de-differentiated cells. in de-differentiated cells,nrf2 is not activated by oxidation but rather through a noncanonical mechanism involving its phosphorylation by the er membrane kinase perk. in contrast,differentiated cells require oxidative damage to activate nrf2. constitutive perk-nrf2 signaling protects de-differentiated cells from chemotherapy by reducing ros levels and increasing drug efflux. these findings are validated in therapy-resistant basal breast cancer cell lines and animal models,where inhibition of the perk-nrf2 signaling axis reversed the mdr of de-differentiated cancer cells. additionally,analysis of patient tumor datasets showed that a perk pathway signature correlates strongly with chemotherapy resistance,tumor grade,and overall survival. collectively,these results indicate that de-differentiated cells up-regulate mdr genes via perk-nrf2 signaling and suggest that targeting this pathway could sensitize drug-resistant cells to chemotherapy. © 2014 del vecchio et al.