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

ABSTRACT: 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-?B was higher in HSF-1(-/-) mice. I?B, the NF-?B inhibitor, was depleted due to enhanced I?B kinase (IKK)-? 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-?B 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.

SUBMITTER: Krishnamurthy K 

PROVIDER: S-EPMC3384141 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature