Heat shock factor-1 knockout induces multidrug resistance gene, MDR1b, and enhances P-glycoprotein (ABCB1)-based drug extrusion in the heart

• Published in: Proceedings of the National Academy of Sciences - PNAS 2012-06, Vol.109 (23), p.9023-9028
• Main Authors: Krishnamurthy, Karthikeyan, Vedam, Kaushik, Kanagasabai, Ragu, Druhan, Lawrence J., Ilangovan, Govindasamy
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; ATP Binding Cassette Transporter, Subfamily B - antagonists & inhibitors; ATP Binding Cassette Transporter, Subfamily B - genetics; ATP Binding Cassette Transporter, Subfamily B - metabolism; ATP-Binding Cassette Sub-Family B Member 4; Binding sites; Biological Sciences; Cancer; Cardiovascular agents; Cell lines; Doxorubicin - adverse effects; Drug resistance; Fluorescence; Gene expression; Gene Expression Regulation - genetics; Glycoproteins; Heart; Heart failure; Heart Failure - chemically induced; Heart Failure - metabolism; Heat-Shock Proteins - genetics; Mice; Mice, Inbred BALB C; Mice, Knockout; Molecular Chaperones; Myocardium; Myocytes, Cardiac - metabolism; Neoplasm Proteins - genetics; Rodents; Shock heating; Transcription factors; Transcriptional regulatory elements; Ventricular Function, Left - drug effects; Verapamil - pharmacology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1200731109

Heat-shock factor 1 (HSF-1), a transcription factor for heat-shock proteins (HSPs), is known to interfere with the transcriptional activity of many oncogenic factors. In the present work, we have discovered that HSF-1 ablation induced the multidrug resistance gene, MDR1b, in the heart and increased the expression of P-glycoprotein (P-gp, ABCB1), an ATP binding cassette that is usually associated with multidrug-resistant cancer cells. The increase in P-gp enhanced the extrusion of doxorubicin (Dox) to alleviate Dox-induced heart failure and reduce mortality in mice. Dox-induced left ventricular (LV) dysfunction was significantly reduced in HSF-1⁻/⁻ mice. DNA binding activity of NF-κB was higher in HSF-1⁻/⁻ mice. IκB, the NFκB inhibitor, was depleted due to enhanced IκB kinase (IKK)-α activity. In parallel, MDR1b gene expression and a large increase in P-gp and lowering Dox loading were observed in HSF-1⁻/⁻ mouse hearts. Moreover, application of the P-gp antagonist verapamil, increased Dox loading in HSF-1⁻/⁻ cardiomyocytes, deteriorated cardiac function in HSF-1⁻/⁻ mice, and decreased survival. MDR1 promoter activity was higher in HSF-1⁻/⁻ cardiomyocytes, whereas a mutant MDR1 promoter with heat-shock element (HSE) mutation showed increased activity only in HSF-1⁺/⁺ cardiomyocytes. However, deletion of HSE and NF-κB binding sites diminished luminescence in both HSF-1⁺/⁺ and HSF-1⁻/⁻ cardiomyocytes, suggesting that HSF-1 inhibits MDR1 activity in the heart. Thus, because high levels of HSF-1 are attributed to poor prognosis of cancer, systemic down-regulation of HSF-1 before chemotherapy is a potential therapeutic approach to ameliorate the chemotherapy-induced cardiotoxicity and enhance cancer prognosis.