Naturally Occurring Isothiocyanates Exert Anticancer Effects by Inhibiting Deubiquitinating Enzymes.
Naturally Occurring Isothiocyanates Exert Anticancer Effects by Inhibiting Deubiquitinating Enzymes.
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DOI：
10.1158/0008-5472.can-15-1544
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发表时间：
2015-12-01
期刊：
影响因子：
11.2
通讯作者：
Hedstrom L
中科院分区：
文献类型：
--
作者：
Lawson AP;Long MJC;Coffey RT;Qian Y;Weerapana E;El Oualid F;Hedstrom L
十字花科蔬菜的抗癌特性是众所周知的，并归因于丰富的异硫氰酸酯（ITC），如苄基ITC（BITC）和苯乙基ITC（PEITC）。虽然已经提出了许多ITCs的潜在靶点，但对其抗癌活性的机制的充分理解仍然是难以捉摸的。在这里，我们报告说，BITC和PEITC有效地抑制去泛素化酶（DUBs），包括酶USP 9 x和UCH 37，这是与肿瘤发生，在生理相关的浓度和时间尺度。USP 9 x保护抗凋亡蛋白Mcl-1免于降解，并且依赖于Mcl-1的细胞对BITC和PEITC特别敏感。这些ITC增加了Mcl-1泛素化，并且ITC处理或RNAi介导的USP 9 x沉默降低了Mcl-1水平，这与USP 9 x是ITC活性的主要靶标的观点一致。这些ITC也增加了致癌融合蛋白Bcr-Abl的泛素化，导致在低ITC浓度下降解和在高ITC浓度下聚集。USP 9 x抑制ITC处理诱导的Bcr-Abl水平降低，USP 9 x沉默足以降低Bcr-Abl水平，进一步表明Bcr-Abl是USP 9 x底物。总的来说，我们的研究结果表明，USP 9 x靶向对ITC公认的抗癌活性的基础机制至关重要。我们认为ITC诱导的DUB抑制也可以解释ITC如何影响炎症和DNA修复过程，从而为理解ITC治疗癌症以及各种其他病理条件的功能和有用应用提供了一个统一的主题。
The anticancer properties of cruciferous vegetables are well known and attributed to an abundance of isothiocyanates (ITCs) such as benzyl ITC (BITC) and phenethyl ITC (PEITC). While many potential targets of ITCs have been proposed, a full understanding of the mechanisms underlying their anticancer activity has remained elusive. Here we report that BITC and PEITC effectively inhibit deubiquitinating enzymes (DUBs), including the enzymes USP9x and UCH37, which are associated with tumorigenesis, at physiologically relevant concentrations and time scales. USP9x protects the anti-apoptotic protein Mcl-1 from degradation, and cells dependent on Mcl-1 were especially sensitive to BITC and PEITC. These ITCs increased Mcl-1 ubiquitination and either ITC treatment or RNAi-mediated silencing of USP9x decreased Mcl-1 levels, consistent with the notion that USP9x is a primary target of ITC activity. These ITCs also increased ubiquitination of the oncogenic fusion protein Bcr-Abl, resulting in degradation under low ITC concentrations and aggregation under high ITC concentrations. USP9x inhibition paralleled the decrease in Bcr-Abl levels induced by ITC treatment, and USP9x silencing was sufficient to decrease Bcr-Abl levels, further suggesting that Bcr-Abl is a USP9x substrate. Overall, our findings suggest that USP9x targeting is critical to the mechanism underpinning the well established anticancer activity of ITC. We propose that the ITC-induced inhibition of DUB may also explain how ITCs affect inflammatory and DNA repair processes, thus offering a unifying theme in understanding the function and useful application of ITCs to treat cancer as well as a variety of other pathological conditions.