Abstract

Physiological stress conditions associated with the tumor microenvironment play a role in resistance to anticancer therapy. In this study, treatment of EMT6 mouse mammary tumor cells with hypoxia or the chemical stress agents brefeldin A (BFA) or okadaic acid (OA) causes the development of resistance to the topoisomerase II inhibitor etoposide. The mechanism of physiological stress-induced drug resistance may involve the activation of stress-responsive proteins and transcription factors. Our previous work shows that treatment with BFA or OA causes activation of the nuclear transcription factor NF-κB. Pretreatment with the proteasome inhibitor carbobenzyoxyl-leucinyl-leucinyl-leucinal inhibits stress-induced NF-κB activation and reverses BFA-induced drug resistance. To test whether NF-κB specifically mediates stress-induced drug resistance, an inducible phosphorylation site-deficient mutant of IκBα (IκBαM, S32/36A) was introduced into EMT6 cells. In this study, we show that IκBαM expression inhibits stress-induced NF-κB activation and prevents BFA-, hypoxia-, and OA-induced resistance to etoposide. These results indicate that NF-κB activation mediates both chemical and physiological drug resistance to etoposide. Furthermore, they imply that coadministration of agents that inhibit NF-κB may enhance the efficacy of topoisomerase II inhibitors in clinical cancer chemotherapy.