Abstract
Heat shock factor-1 (HSF-1), a transcription factor of heat shock proteins, is known to interfere with the transcriptional activity of many oncogenic and anti-inflammatory factors. In the present work we have discovered that HSF-1 ablation induced 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, and it could successfully extrude doxorubicin (Dox) to alleviate Dox-induced heart failure and reduce mortality in mice. Cardiac MRI showed that Dox-induced left ventricular dysfunction was significantly reduced in HSF-1 -/- mice. NF-B nuclear translocation and DNA binding activity were higher in Dox-treated HSF-1 -/- mice. IB, the NF-B inhibitor, was depleted due to enhanced 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. However, 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 (as determined by luciferase reporter gene assay), was higher in HSF-1 -/- cardiomyocytes, whereas a mutant MDR1 promoter with heat shock elements (HSE) mutation showed increased activity only in HSF-1 +/+ cardiomyocytes. However, deletion of both HSE and NF- κB binding motifs diminished the luciferase luminescence, suggesting that HSF-1 competitively inhibits MDR1 promoter activity. Thus, since high levels of HSF-1 is attributed to poor prognosis of cancer, systemic down regulation of HSF-1 before chemotherapy is a potential therapeutic approach to ameliorate the chemotherapeutics-induced cardiotoxicity and enhance cancer prognosis.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
