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Heat Shock Factor-1 Knockout Induces Multidrug Resistance Gene, Mdr1b, and Enhances P-Glycoprotein (ABCB1)-Based Drug Extrusion in the Heart

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Heat Shock Factor-1 Knockout Induces Multidrug Resistance Gene, Mdr1b, and Enhances P-Glycoprotein (ABCB1)-Based Drug Extrusion in the Heart Heat shock factor-1 knockout induces multidrug resistance gene, MDR1b, and enhances P-glycoprotein (ABCB1)-based drug extrusion in the heart Karthikeyan Krishnamurthya, Kaushik Vedama,1, Ragu Kanagasabaia,1, Lawrence J. Druhanb, and Govindasamy Ilangovana,2 Departments of aInternal Medicine and bAnesthesiology, Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210 Edited by Lawrence H. Einhorn, Indiana University, Indianapolis, IN, and approved April 23, 2012 (received for review January 18, 2012) Heat-shock factor 1 (HSF-1), a transcription factor for heat-shock from Dox by inducing the multidrug-resistant gene 1 (MDR1) and proteins (HSPs), is known to interfere with the transcriptional activ- expression of P-glycoprotein (P-gp), an ATP-binding cassette ity of many oncogenic factors. In the present work, we have discov- (ABCB1) transporter, which is usually associated with multidrug- ered that HSF-1 ablation induced the multidrug resistance gene, resistant cancer cells, and we found that it actively extrudes Dox MDR1b, in the heart and increased the expression of P-glycoprotein from cardiomyocytes in HSF-1 knockout mouse hearts. (P-gp, ABCB1), an ATP binding cassette that is usually associated HSF-1 is an immediate responder of any intrinsic or extrinsic with multidrug-resistant cancer cells. The increase in P-gp enhanced stress, and it enhances expression of heat-shock proteins (HSPs). the extrusion of doxorubicin (Dox) to alleviate Dox-induced heart This response is generally considered an act of stress tolerance, so failure and reduce mortality in mice. Dox-induced left ventricular that the cells can recover from the exerted stress and survive (12). − − (LV) dysfunction was significantly reduced in HSF-1 / mice. DNA- Many studies have found that preinduction of Hsp25 (a member of − − binding activity of NF-κB was higher in HSF-1 / mice. IκB, the NF- the small heat-shock protein family that is linked to cell apoptosis), κB inhibitor, was depleted due to enhanced IκBkinase(IKK)-α ac- by either HSF-1 activation before inflammation or by over- tivity. In parallel, MDR1b gene expression and a large increase in P- expression methods, is cytoprotective, whereas Hsp25 induction −/− gp and lowering Dox loading were observed in HSF-1 mouse postinflammation is cytotoxic (13). This “heat-shock paradox” is hearts. Moreover, application of the P-gp antagonist, verapamil, poorly understood at present, especially in relation to Dox-induced −/− increased Dox loading in HSF-1 cardiomyocytes, deteriorated car- heart failure (13). Understanding the role of HSF-1 in the heart is −/− diac function in HSF-1 mice, and decreased survival. MDR1 pro- further complicated by the fact that HSF-1 can indirectly regulate −/− moter activity was higher in HSF-1 cardiomyocytes, whereas the transcriptional activity of another transcription factor, nuclear a mutant MDR1 promoter with heat-shock element (HSE) mutation κ κ – +/+ factor- B(NF- B) (14 16). The DNA-binding sites for HSF-1 and showed increased activity only in HSF-1 cardiomyocytes. How- NF-κB show close homology; as such, they can mutually influence ever, deletion of HSE and NF-κB binding sites diminished lumines- κ +/+ −/− DNA binding. NF- B has been shown to promote expression of cenceinbothHSF-1 and HSF-1 cardiomyocytes, suggesting heat-shock genes (14), but not in response to heat stress (17). that HSF-1 inhibits MDR1 activity in the heart. Thus, because high P-gp, a product of MDR1, protects multidrug-resistant cancer levels of HSF-1 are attributed to poor prognosis of cancer, systemic cells by extruding the antineoplastic agents. The MDR1 promoter down-regulation of HSF-1 before chemotherapy is a potential ther- has been shown to have NF-κB binding, and multiple binding sites apeutic approach to ameliorate the chemotherapy-induced cardio- for heat-shock transcription factors, termed heat-shock elements toxicity and enhance cancer prognosis. (HSEs). Because HSF-1 is activated by Dox in the heart (11), here we tested a unique hypothesis that HSF-1 binding to HSEs in the GENETICS dilated cardiomyopathy | oxidative stress | mouse model of MDR1 promoter would repress MDR1 gene expression by an- cardioprotection | chemotherapeutics tagonizing the NF-κB binding site. The dogma for HSF-1 knock- out is that it should enhance Dox-induced cell death in the heart nthracyclines such as doxorubicin (Dox) and its derivatives due to the expected decrease in defense against Dox-induced Aare used as antineoplastics, either alone or in combination oxidative stress. However, our results show an atypical pathway with other drugs, to treat many types of cancer. Although Dox is wherein the ablation of HSF-1 indeed provided cardioprotection, an effective chemotherapeutic drug, it has long been known to by increasing NF-κB transactivation and enhanced MDR1 gene cause severe cardiotoxicity, leading to dilated cardiomyopathy expression to establish P-gp–based drug extrusion in the heart. and congestive heart failure (1). Despite recent improvements of the drug, clinical manifestation of cardiac dysfunction among Results − − Dox-treated cancer patients still persists as a serious side effect. MDR1b Gene Expression and Dox Extrusion in HSF-1 / Mouse Hearts. Other classes of chemotherapeutics, including tyrosine kinase Fig. 1A shows the Western blots of P-gp in HSF-1 wild-type and inhibitors (TKIs) such as imatinib mesylate and humanized an- knockout mice (Fig. S1). P-gp level (both 150 kDa and 170 kDa, tibody-based therapeutics such as trastuzumab have also been found to cause significant cardiotoxicity (2, 3). In the case of Dox, the cardiotoxicity has been considered to be primarily due Author contributions: K.K., K.V., R.K., and G.I. designed research; K.K., K.V., and R.K. to oxidative-stress–induced death of cardiomyocytes and subsequent performed research; L.J.D. contributed new reagents/analytic tools; K.K., K.V., L.J.D., irreversible myocardial remodeling. However, many clinical trials and G.I. analyzed data; and K.K., L.J.D., and G.I. wrote the paper. testing the effectiveness of antioxidants indicated no significant The authors declare no conflict of interest. cardioprotection during Dox treatment (4). Thus, alternate strat- This article is a PNAS Direct Submission. fi egies, based on other identi ed pathways, are warranted to over- 1K.V. and R.K. contributed equally to this work. fi come this deleterious effect. Recent studies have identi ed several 2To whom correspondence should be addressed. E-mail: Govindasamy.Ilangovan@osumc. pathways of Dox-induced myocardial remodeling, including the edu. – involvement of heat-shock factor 1 (HSF-1) (5 11). Here we report This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. a unique finding that HSF-1 knockout provided cardioprotection 1073/pnas.1200731109/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1200731109 PNAS | June 5, 2012 | vol. 109 | no. 23 | 9023–9028 Downloaded by guest on September 26, 2021 − − Fig. 1. MDR1/P-gp expression in HSF-1 / hearts. (A) Western blots of P-gp in heart tissue lysates of HSF-1+/+ and HSF-1−/− mice. (B) RT-PCR assessment of MDR1a and MDR1b mRNAs. (C) Multimodal fluorescence of α-actin and P-gp − − in Dox-treated HSF-1+/+ and HSF-1 / mouse heart tissues (green, Alexa Fluor 488, α-actin; red, Alexa Fluor 555, P-gp; blue, DAPI, nuclei). corresponding to fully glycosylated and lesser glycosylated iso- − − forms) (18) was very high in HSF-1 / mouse hearts. RT-PCR +/+ −/− assessment of MDR1a and MDR1b (isoforms known to be in Fig. 2. MDR1 promoter activity in HSF-1 and HSF-1 cardiomyocytes. (A) murine muscle tissues) mRNA showed higher MDR1b (the in- Schematics of luciferase lentiviral construct with human MDR1 promoter ducible isoform −/− B subcloned as replacement of PGK1 promoter in pLentiPGKV5Luci expression ) expression in HSF-1 hearts (Fig. 1 ), sug- vector. WT-MDR1 promoter has overlapping HSF-1 and NF-κB binding sites gesting that ablation of HSF-1 induces a multidrug-resistant (–174 to –153). Mut-MDR1 prom1 was generated by site-directed mutagen- phenotype in the heart. Coimmunofluorescence staining of P-gp esis, to ablate the HSF-1 binding site, and Mut-MDR1 prom2 was generated +/+ −/− and α-actin (cardiomyocyte specific) in HSF-1 and HSF-1 by deleting both HSF-1 and NF-kB binding sites (Table S1). (B) Quantitative mouse heart tissues (merged images in Fig. 1C) confirmed higher plots (n = 4) are the luminescence measured from HSF-1+/+ and HSF-1−/− − − P-gp expression in cardiomyocytes of HSF-1 / mice. cardiomyocytes transduced with the WT-MDR1 and Mut-MDR1 promoter Transcriptional regulation of MDR1 gene/P-gp expression by containing luciferase viral vectors. HSF-1 was studied using a luciferase reporter gene assay. In the MDR1 promoter, a HSE is found to be upstream of a NF-κB binding site, between −174 and −153 (Fig. 2A). The proximal 10 nM. However, there was no induction of P-gp at any con- promoter region of the human MDR1 gene (Fig. S2) was cloned centration of siRNA used (Fig. 3). and used as the promoter for the luciferase gene in a lentiviral − − In Vitro P-gp Pump Action and Dox Extrusion in HSF-1 / Mouse vector (Fig. 2A). Adult cardiomyocytes from HSF-1+/+ and − − Cardiomyocytes. To demonstrate the function of P-gp as a Dox HSF-1 / mice were transduced with pLenti-MDR1pro-Luci vi- efflux pump in the heart, the Dox loading level in isolated adult rus and the luciferase activity was determined. The luminescence +/+ −/− − − was close to fivefold higher in HSF-1 / cardiomyocytes, relative mouse cardiomyocytes from HSF-1 and HSF-1 mice was B determined using Dox autofluorescence (18, 19). Isolated adult to wild type (Fig. 2 ). When the HSE (GAACTTTC) in the +/+ −/− A cardiomyocytes from HSF-1 and HSF-1 mice were treated MDR1 promoter was mutated (GACCATAC) (Fig.
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