Unleashing the full potential of Hsp90 inhibitors as cancer therapeutics through simultaneous inactivation of Hsp90, Grp94, and TRAP1
Unleashing the full potential of Hsp90 inhibitors as cancer therapeutics through simultaneous inactivation of Hsp90, Grp94, and TRAP1
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DOI：
10.1038/s12276-019-0360-x
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发表时间：
2020-01-20
影响因子：
12.8
通讯作者：
Kang, Byoung Heon
中科院分区：
文献类型：
--
作者：
Park, Hye-Kyung;Yoon, Nam Gu;Kang, Byoung Heon
癌症治疗：一种阻断热休克蛋白（HSPs）的新药显示了癌症治疗的希望。热休克蛋白是癌细胞促进肿瘤生长的辅助蛋白。几种药物已经靶向了热休克蛋白，因为已知癌细胞会劫持这些辅助蛋白来保护自己免受身体的破坏。然而，这些药物的成功有限。韩国蔚山国立科学技术研究院的Hye-Kyung Park和Byoung Heon Kang及其同事注意到，这些药物没有被吸收到线粒体中，线粒体是一个关键的细胞区室，因此这个区室中的HSP没有被阻断。他们发现了一种新的HSP抑制剂，可以到达每个细胞区室并抑制所有HSP。在小鼠中的测试表明，这种抑制剂有效地触发肿瘤细胞的死亡，因此显示出抗癌治疗的前景。Hsp 90家族蛋白Hsp 90，Grp 94和TRAP 1分别存在于细胞质，内质网和线粒体中;所有通过调节蛋白质稳态响应于应激在肿瘤发生中发挥重要作用。因此，同时抑制所有Hsp 90旁系同源物是癌症治疗的合理策略。然而，由于现有的pan-Hsp 90抑制剂不在线粒体中积累，因此pan-Hsp 90抑制的潜在抗癌活性尚未在体内充分研究。癌症基因组图谱数据库的分析显示，所有Hsp 90旁系同源物在前列腺癌中上调。所有Hsp 90旁系同源物的失活诱导线粒体功能障碍，增加胞浆钙，并激活钙调神经磷酸酶。活性钙调神经磷酸酶通过阻止HSF 1的核转位阻断Hsp 90抑制后的促存活热休克反应。嘌呤支架衍生物DN 401同时抑制所有Hsp 90旁系同源物，并显示出比其他Hsp 90抑制剂更强的抗癌活性。Pan-Hsp 90抑制增加了细胞毒性并抑制了保护癌细胞的机制，这表明它是开发有效抗癌药物的可行策略。透水药物DN 401是一种新发现的体内泛热休克蛋白90抑制剂，具有有效的抗癌活性。
Cancer therapeutics: Extending a drug's reach A new drug that blocks heat shock proteins (HSPs), helper proteins that are co-opted by cancer cells to promote tumor growth, shows promise for cancer treatment. Several drugs have targeted HSPs, since cancer cells are known to hijack these helper proteins to shield themselves from destruction by the body. However, the drugs have had limited success. Hye-Kyung Park and Byoung Heon Kang at Ulsan National Institutes of Science and Technology in South Korea and coworkers noticed that the drugs were not absorbed into mitochondria, a key cellular compartment, and HSPs in this compartment were therefore not being blocked. They identified a new HSP inhibitor that can reach every cellular compartment and inhibit all HSPs. Testing in mice showed that this inhibitor effectively triggered death of tumor cells, and therefore shows promise for anti-cancer therapy.The Hsp90 family proteins Hsp90, Grp94, and TRAP1 are present in the cell cytoplasm, endoplasmic reticulum, and mitochondria, respectively; all play important roles in tumorigenesis by regulating protein homeostasis in response to stress. Thus, simultaneous inhibition of all Hsp90 paralogs is a reasonable strategy for cancer therapy. However, since the existing pan-Hsp90 inhibitor does not accumulate in mitochondria, the potential anticancer activity of pan-Hsp90 inhibition has not yet been fully examined in vivo. Analysis of The Cancer Genome Atlas database revealed that all Hsp90 paralogs were upregulated in prostate cancer. Inactivation of all Hsp90 paralogs induced mitochondrial dysfunction, increased cytosolic calcium, and activated calcineurin. Active calcineurin blocked prosurvival heat shock responses upon Hsp90 inhibition by preventing nuclear translocation of HSF1. The purine scaffold derivative DN401 inhibited all Hsp90 paralogs simultaneously and showed stronger anticancer activity than other Hsp90 inhibitors. Pan-Hsp90 inhibition increased cytotoxicity and suppressed mechanisms that protect cancer cells, suggesting that it is a feasible strategy for the development of potent anticancer drugs. The mitochondria-permeable drug DN401 is a newly identified in vivo pan-Hsp90 inhibitor with potent anticancer activity.