Abstract
Mutant p53 accumulation has been shown to induce the multidrug resistance gene (MDR1) and ATP binding cassette (ABC)-based drug efflux in human breast cancer cells. In the present work, we have found that transcriptional activation of the oxidative stress-responsive heat shock factor 1 (HSF-1) and expression of heat shock proteins, including Hsp27, which is normally known to augment proteasomal p53 degradation, are inhibited in Adriamycin (doxorubicin)-resistant MCF-7 cells (MCF-7/adr). Such an endogenous inhibition of HSF-1 and Hsp27 in turn results in p53 mutation with gain of function in its transcriptional activity and accumulation in MCF-7/adr. Also, lack of HSF-1 enhances nuclear factor κB (NF-κB) DNA binding activity together with mutant p53 and induces MDR1 gene and P-glycoprotein (P-gp, ABCB1), resulting in a multidrug-resistant phenotype. Ectopic expression of Hsp27, however, significantly depleted both mutant p53 and NF-κB (p65), reversed the drug resistance by inhibiting MDR1/P-gp expression in MCF-7/adr cells, and induced cell death by increased G(2)/M population and apoptosis. We conclude from these results that HSF-1 inhibition and depletion of Hsp27 is a trigger, at least in part, for the accumulation of transcriptionally active mutant p53, which can either directly or NF-κB-dependently induce an MDR1/P-gp phenotype in MCF-7 cells. Upon Hsp27 overexpression, this pathway is abrogated, and the acquired multidrug resistance is significantly abolished so that MCF-7/adr cells are sensitized to Dox. Thus, clinical alteration in Hsp27 or NF-κB level will be a potential approach to circumvent drug resistance in breast cancer.
Highlights
Grants R21 HL094881 and R01 HL078796-02. □S The on-line version of this article contains supplemental Tables 1 and 2 and Figs. 1–3. 1 To whom correspondence should be addressed: 392 Biomedical Research
The present work has revealed that chronic exposure of the human breast cancer cell line, MCF-7, to Dox inhibits heat shock factor 1 (HSF-1) expression and its transactivation, leading to decreased heat shock protein 27 (Hsp27)
The absence of Hsp27, which is required for p53 proteasomal degradation by ubiquitination [39], results in accumulation of mutp53, and that in turn triggers the nuclear factor B (NF-B)-dependent signaling pathway to induce MDR1 gene and P-gp efflux pumps in MCF-7/adr cells
Summary
Grants R21 HL094881 and R01 HL078796-02. □S The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables 1 and 2 and Figs. 1–3. 1 To whom correspondence should be addressed: 392 Biomedical Research. Drug resistance is acquired via direct suppression of apoptotic pathways due to accumulation of mutant p53 (mutp53) with “gain of function” [7, 8] and increased expression of antiapoptotic proteins, such as BCl-2 [4]. Wild type p53 is generally known to repress the expression of the MDR1 gene, which codes for the ABC protein P-gp through interaction with basal transcription factors, such as TATA-binding protein [13]. Mutant p53 has been demonstrated to activate the MDR1 promoter probably by both dominant negative and gain of function mechanisms [16]. Understanding of the roles of other p53-dependent mediators of drug resistance, especially mediators of ABC induction, in breast cancer cells still remains elusive. Mutant p53 and NF-B may have a strong relationship with other stress-responsive factors in the overall multidrug resistance scheme
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