Forced Expression of Heat Shock Protein 27 (Hsp27) Reverses P-Glycoprotein (ABCB1)-mediated Drug Efflux and MDR1 Gene Expression in Adriamycin-resistant Human Breast Cancer Cells

• Published in: The Journal of biological chemistry 2011-09, Vol.286 (38), p.33289-33300
• Main Authors: Kanagasabai, Ragu, Krishnamurthy, Karthikeyan, Druhan, Lawrence J., Ilangovan, Govindasamy
• Format: Article
• Language: English
• Subjects: ABC Transporter; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; Breast Cancer; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer Therapy; Cell Death - drug effects; Cell Line, Tumor; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - metabolism; Doxorubicin - metabolism; Doxorubicin - pharmacology; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Enzyme Activation - drug effects; Female; Gene Expression Regulation, Neoplastic - drug effects; Heat Shock Factor-1; Heat Shock Protein; Heat Shock Transcription Factors; Heat-Shock Proteins; HSP27 Heat-Shock Proteins - deficiency; HSP27 Heat-Shock Proteins - metabolism; Humans; Intracellular Space - drug effects; Intracellular Space - metabolism; Mitogen-Activated Protein Kinases - metabolism; Models, Biological; Molecular Bases of Disease; Molecular Chaperones; Mutant p53; Mutant Proteins - metabolism; NF-kappa B - metabolism; p53; Phosphorylation - drug effects; Signal Transduction - drug effects; Transcription Factors - antagonists & inhibitors; Transcription Factors - metabolism; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.249102

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 G2/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.