NF-kappaB transcription factor induces drug resistance through MDR1 expression in cancer cells.
The ubiquitous NF-kappaB transcription factor has been reported to inhibit apoptosis and to induce drug resistance in cancer cells. Drug resistance is the major reason for cancer therapy failure and neoplastic cells often develop multiple mechanisms of drug resistance during tumor progression. We observed that NF-kappaB or P-glycoprotein inhibition in the HCT15 colon cancer cells led to increased apoptotic cell death in response to daunomycin treatment. Interestingly, NF-kappaB inhibition through transfection of a plasmid coding for a mutated IkappaB-alpha inhibitor increased daunomycin cell uptake. Indeed, the inhibition of NF-kappaB reduced mdr1 mRNA and P-glycoprotein expression in HCT15 cells. We identified a consensus NF-kappaB binding site in the first intron of the human mdr1 gene and demonstrated that NF-kappaB complexes could bind with this intronic site. Moreover, NF-kappaB transactivates an mdr1 promoter luciferase construct. Our data thus demonstrate a role for NF-kappaB in the regulation of the mdr1 gene expression in cancer cells and in drug resistance.
Bentires-Alj
Mohamed
M
Center for Cellular and Molecular Therapy, University of Liége, Belgium.
Barbu
Veronique
V
Fillet
Marianne
M
Chariot
Alain
A
Relic
Biserka
B
Jacobs
Nathalie
N
Gielen
Jacques
J
Merville
Marie-Paule
MP
Bours
Vincent
V
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D017931:DNA Primers; D003630:Daunorubicin / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D007438:Introns; D016328:NF-kappa B / Q000502:physiology*; D010957:Plasmids; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation / Q000502:physiology; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D017931:DNA Primers; D016328:NF-kappa B; D003630:Daunorubicin