Reversal of physiological stress-induced resistance to topoisomerase II inhibitors using an inducible phosphorylation site-deficient mutant of I kappa B alpha.
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-kappa B. Pretreatment with the proteasome inhibitor carbobenzyoxyl-leucinyl-leucinyl-leucinal inhibits stress-induced NF-kappa B activation and reverses BFA-induced drug resistance. To test whether NF-kappa B specifically mediates stress-induced drug resistance, an inducible phosphorylation site-deficient mutant of I kappa B alpha (I kappa B alpha M, S32/36A) was introduced into EMT6 cells. In this study, we show that I kappa B alpha M expression inhibits stress-induced NF-kappa B activation and prevents BFA-, hypoxia-, and OA-induced resistance to etoposide. These results indicate that NF-kappa B activation mediates both chemical and physiological drug resistance to etoposide. Furthermore, they imply that coadministration of agents that inhibit NF-kappa B may enhance the efficacy of topoisomerase II inhibitors in clinical cancer chemotherapy.
Brandes
L M
LM
Department of Pharmacology, The George Washington University Medical Center, Washington, DC 20037, USA.
Lin
Z P
ZP
Patierno
S R
SR
Kennedy
K A
KA
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D020126:Brefeldin A / Q000494:pharmacology; D015687:Cell Hypoxia; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005047:Etoposide / Q000494:pharmacology*; D020672:I-kappa B Proteins; D051379:Mice; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D019319:Okadaic Acid / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism*; D010766:Phosphorylation; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha; D019319:Okadaic Acid; D020126:Brefeldin A; D005047:Etoposide; D010100:Oxygen