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首页> 外文期刊>Cancer Cell >Overcoming intrinsic multidrug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1Bhigh cells
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Overcoming intrinsic multidrug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1Bhigh cells

机译：通过阻断慢循环JARID1Bhigh细胞的线粒体呼吸链来克服黑色素瘤固有的多药耐药性

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摘要

Despite success with BRAFV600E inhibitors, therapeutic responses in patients with metastatic melanoma are short-lived because of the acquisition of drug resistance. We identified a mechanism of intrinsic multidrug resistance based on the survival of a tumor cell subpopulation. Treatment with various drugs, including cisplatin and vemurafenib, uniformly leads to enrichment of slow-cycling, long-term tumor-maintaining melanoma cells expressing the H3K4-demethylase JARID1B/KDM5B/PLU-1. Proteome-profiling revealed an upregulation in enzymes of mitochondrial oxidative-ATP-synthesis (oxidative phosphorylation) in this subpopulation. Inhibition of mitochondrial respiration blocked the emergence of the JARID1Bhigh subpopulation and sensitized melanoma cells to therapy, independent of their genotype. Our findings support a two-tiered approach combining anticancer agents that eliminate rapidly proliferating melanoma cells with inhibitors of the drug-resistant slow-cycling subpopulation.
机译：尽管使用BRAFV600E抑制剂取得了成功，但由于获得了耐药性，转移性黑色素瘤患者的治疗反应仍然短暂。我们确定了基于肿瘤细胞亚群生存的内在多药耐药性的机制。用各种药物（包括顺铂和维罗非尼）进行治疗，可统一导致表达H3K4-脱甲基酶JARID1B / KDM5B / PLU-1的慢循环，长期维持肿瘤的黑色素瘤细胞的富集。蛋白质组图谱显示该亚群中线粒体氧化ATP合成酶（氧化磷酸化）的表达上调。抑制线粒体呼吸阻止了JARID1Bhigh亚群的出现，并使黑素瘤细胞对治疗敏感，而与它们的基因型无关。我们的发现支持采用两层方法，将消除快速增殖的黑色素瘤细胞的抗癌药与耐药性慢循环亚群抑制剂结合使用。

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