Overcoming intrinsic multidrug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1B(high) cells.
Overcoming intrinsic multidrug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1B(high) cells.
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DOI：
10.1016/j.ccr.2013.05.003
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发表时间：
2013-06-10
期刊：
影响因子：
50.3
通讯作者：
Herlyn M
中科院分区：
文献类型：
--
作者：
Roesch A;Vultur A;Bogeski I;Wang H;Zimmermann KM;Speicher D;Körbel C;Laschke MW;Gimotty PA;Philipp SE;Krause E;Pätzold S;Villanueva J;Krepler C;Fukunaga-Kalabis M;Hoth M;Bastian BC;Vogt T;Herlyn M
尽管BRAFV 600 E抑制剂取得了成功，但由于获得耐药性，转移性黑色素瘤患者的治疗反应是短暂的。我们基于肿瘤细胞亚群的存活确定了内在多药耐药机制。用包括顺铂和vemurafenib在内的各种药物治疗，均匀地导致表达H3 K4-去甲基化酶JARID 1B/KDM 5 B/PLU-1的慢循环、长期肿瘤维持的黑色素瘤细胞的富集。蛋白质组分析显示，在这个亚群的线粒体氧化ATP合成（OXPHOS）的酶的上调。线粒体呼吸抑制阻断了JARID 1Bhigh亚群的出现，并使黑色素瘤细胞对治疗敏感，与其基因型无关。我们的研究结果支持一个两层的方法相结合的抗癌药物，消除快速增殖的黑色素瘤细胞与耐药慢循环亚群的抑制剂。
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 multi-drug 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 (OXPHOS) 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 anti-cancer agents that eliminate rapidly proliferating melanoma cells with inhibitors of the drug-resistant slow-cycling subpopulation.
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影响因子：
64.5
作者：
Roesch A;Fukunaga-Kalabis M;Schmidt EC;Zabierowski SE;Brafford PA;Vultur A;Basu D;Gimotty P;Vogt T;Herlyn M
通讯作者：
Herlyn M
DOI：
10.1016/j.bbrc.2004.03.185
发表时间：
2004-05-21
影响因子：
3.1
作者：
Charton, C;Ulaszewski, S;Claisse, ML
通讯作者：
Claisse, ML
苯甲曲作为预防和乳腺癌异种移植的治疗。
影响因子：
8.8
作者：
Appleyard, M. V. C. L.;Murray, K. E.;Coates, P. J.;Wullschleger, S.;Bray, S. E.;Kernohan, N. M.;Fleming, S.;Alessi, D. R.;Thompson, A. M.
通讯作者：
Thompson, A. M.
影响因子：
4.8
作者：
Hao, Wenshan;Chang, Chao-Pei Betty;Xu, Jun
通讯作者：
Xu, Jun
影响因子：
64.5
作者：
Gupta PB;Onder TT;Jiang G;Tao K;Kuperwasser C;Weinberg RA;Lander ES
通讯作者：
Lander ES