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.
Footnotes
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↵1 Current address: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520.
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This work was supported in part by Army Breast Cancer Initiative Award #99–1-9186 (to K.A.K.) and by a faculty research enhancement award from the George Washington University Medical Center (to K.A.K.).
- Abbreviations:
- ER
- endoplasmic reticulum
- EOR
- endoplasmic reticulum-overload response
- NF-κB
- nuclear factor-κB
- BFA
- brefeldin A
- OA
- okadaic acid
- MG-132
- carbobenzyoxyl-leucinyl-leucinyl-leucinal
- EMSA
- electrophoretic mobility shift assay
- HA
- hemagglutinin
- IκBαM
- S32/36A mutant inhibitory nuclear factor-κB protein α
- VCT
- vector lacking IκBαM insert
- TBST
- Tris-buffered saline/Tween 20
- BSA
- bovine serum albumin
- ANOVA
- analysis of variance
- UPR
- unfolded protein response
- Received March 2, 2001.
- Accepted May 22, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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