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
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DOI：
10.1073/pnas.1200731109
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发表时间：
2012-06-05
影响因子：
11.1
通讯作者：
Ilangovan, Govindasamy
中科院分区：
文献类型：
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作者：
Krishnamurthy, Karthikeyan;Vedam, Kaushik;Ilangovan, Govindasamy
热休克因子1（Heat-shock factor 1，HSF-1）是热休克蛋白（Heat-shock proteins，HSPs）的一种转录因子，能干扰多种致癌因子的转录活性。在目前的工作中，我们发现HSF-1消融诱导了心脏中的多药耐药基因MDR 1b，并增加了P-糖蛋白（P-gp，ABCB 1）的表达，这是一种通常与多药耐药癌细胞相关的ATP结合盒。P-gp的增加增强了阿霉素（Dox）的排出，以减轻Dox诱导的心力衰竭并降低小鼠的死亡率。在HSF-1（-/-）小鼠中，Dox诱导的左心室（LV）功能障碍显著减少。NF-κ B B的DNA结合活性在HSF-1（-/-）小鼠中更高。I κ B，NF-κ B抑制剂，由于I κ B激酶（IKK）-α活性增强而耗尽。与此同时，在HSF-1（-/-）小鼠心脏中观察到MDR 1b基因表达和P-gp大量增加以及Dox负荷降低。此外，P-gp拮抗剂维拉帕米的应用增加了HSF-1（-/-）心肌细胞中的Dox负荷，恶化了HSF-1（-/-）小鼠的心脏功能，并降低了存活率。MDR 1启动子活性在HSF-1（-/-）心肌细胞中更高，而具有热休克元件（HSE）突变的突变型MDR 1启动子仅在HSF-1（+/+）心肌细胞中显示活性增加。然而，HSE和NF-κ B结合位点的缺失减少了HSF-1（+/+）和HSF-1（-/-）心肌细胞中的发光，表明HSF-1抑制心脏中的MDR 1活性。因此，由于高水平的HSF-1是癌症预后不良的原因，因此在化疗前全身下调HSF-1是改善化疗诱导的心脏毒性和增强癌症预后的潜在治疗方法。
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-kappa B was higher in HSF-1(-/-) mice. I kappa B, the NF-kappa B inhibitor, was depleted due to enhanced I kappa B kinase (IKK)-alpha 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-kappa 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.