Manumycin A suppresses exosome biogenesis and secretion via targeted inhibition of Ras/Raf/ERK1/2 signaling and hnRNP H1 in castration-resistant prostate cancer cells.
Manumycin A suppresses exosome biogenesis and secretion via targeted inhibition of Ras/Raf/ERK1/2 signaling and hnRNP H1 in castration-resistant prostate cancer cells.
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DOI：
10.1016/j.canlet.2017.08.020
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发表时间：
2017-11-01
期刊：
影响因子：
9.7
通讯作者：
Abdel-Mageed AB
中科院分区：
文献类型：
--
作者：
Datta A;Kim H;Lal M;McGee L;Johnson A;Moustafa AA;Jones JC;Mondal D;Ferrer M;Abdel-Mageed AB
新出现的证据通过致癌因子的运输和干细胞的肿瘤重编程将外来体与癌症进展联系起来。这需要鉴定功能上经过验证的外泌体靶向治疗剂并将其整合到当前的癌症管理方案中。我们在两个文库上采用定量高通量筛选来鉴定外泌体靶向药物; 1280种可商购获得的活性化合物的集合和3300种临床批准的化合物的集合。Manumycin-A（MA）是一种天然微生物代谢产物，被鉴定为去势抵抗性前列腺癌（CRPC）C4-2B而不是正常RWPE-1细胞的外泌体生物发生和分泌的抑制剂。虽然没有观察到对细胞生长的影响，但MA减弱了CRPC细胞的ESCRT-0蛋白Hrs、阿利克斯和Rab 27 a以及外来体生物发生和分泌。MA抑制作用主要通过Ras/Raf/ERK 1/2信号传导的靶向抑制介导。Ras依赖性MA抑制外泌体的生物发生和分泌部分由致癌剪接因子hnRNP H1的ERK依赖性抑制介导。我们的研究结果表明，MA是抑制CRPC细胞外泌体生物合成和分泌的潜在候选药物。
Emerging evidence links exosomes to cancer progression by the trafficking of oncogenic factors and neoplastic reprogramming of stem cells. This necessitates identification and integration of functionally validated exosome-targeting therapeutics into current cancer management regimens. We employed quantitative high throughput screen on two libraries to identify exosome-targeting drugs; a commercially available collection of 1280 pharmacologically active compounds and a collection of 3300 clinically approved compounds. Manumycin-A (MA), a natural microbial metabolite, was identified as an inhibitor of exosome biogenesis and secretion by castration-resistant prostate cancer (CRPC) C4-2B, but not the normal RWPE-1, cells. While no effect was observed on cell growth, MA attenuated ESCRT-0 proteins Hrs, ALIX and Rab27a and exosome biogenesis and secretion by CRPC cells. The MA inhibitory effect is primarily mediated via targeted inhibition of the Ras/Raf/ERK1/2 signaling. The Ras-dependent MA suppression of exosome biogenesis and secretion is partly mediated by ERK-dependent inhibition of the oncogenic splicing factor hnRNP H1. Our findings suggest that MA is a potential drug candidate to suppress exosome biogenesis and secretion by CRPC cells.
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影响因子：
5.2
作者：
Abd Elmageed, Zakaria Y.;Yang, Yijun;Thomas, Raju;Ranjan, Manish;Mondal, Debasis;Moroz, Krzysztof;Fang, Zhide;Rezk, Bashir M.;Moparty, Krishnarao;Sikka, Suresh C.;Sartor, Oliver;Abdel-Mageed, Asim B.
通讯作者：
Abdel-Mageed, Asim B.
DOI：
10.1038/nrc3106
发表时间：
2011-10-13
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
4
作者：
Colombo, Marina;Moita, Catarina;Raposo, Graca
通讯作者：
Raposo, Graca
影响因子：
--
作者：
Chowdhury R;Webber JP;Gurney M;Mason MD;Tabi Z;Clayton A
通讯作者：
Clayton A
剪接因子HNRNP A2通过控制肝细胞癌发育中的A-RAF剪接来激活RAS-MAPK-ERK途径。
DOI：
10.1261/rna.042259.113
发表时间：
2014-04
期刊：
RNA (New York, N.Y.)
影响因子：
--
作者：
Shilo A;Ben Hur V;Denichenko P;Stein I;Pikarsky E;Rauch J;Kolch W;Zender L;Karni R
通讯作者：
Karni R