Comparison of the activity of three different HSP70 inhibitors on apoptosis, cell cycle arrest, autophagy inhibition, and HSP90 inhibition
Comparison of the activity of three different HSP70 inhibitors on apoptosis, cell cycle arrest, autophagy inhibition, and HSP90 inhibition
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DOI：
10.4161/cbt.26720
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发表时间：
2014-02-01
影响因子：
3.6
通讯作者：
Murphy, Maureen E.
中科院分区：
文献类型：
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作者：
Budina-Kolomets, Anna;Balaburski, Gregor M.;Murphy, Maureen E.
伴侣HSP 70促进暴露于许多不同类型应激的细胞的存活，并且还具有强效的抗凋亡作用。这种蛋白质的主要应激诱导形式HSP 70 -1在许多人类癌症中过表达，但在正常细胞中表达可忽略不计。沉默编码HSP 70 -1（HSPA 1A）的基因对转化细胞有细胞毒性，但对正常细胞无细胞毒性。因此，HSP 70被认为是一个有前途的癌症药物靶点，并且对用于癌症治疗的HSP 70抑制剂的鉴定和表征一直有着积极的兴趣。由于HSP 70在蛋白质折叠的控制中以相对非特异性的方式起作用，迄今为止还没有可靠鉴定的这种蛋白质的“客户”，也没有关于HSP 70抑制剂对癌细胞的表型效应的共识。在这里，我们首次比较了三种最近发现的HSP 70抑制剂PES-C1、MKT-077和Ver-155008影响该伴侣蛋白的一些已知和报道功能的能力;特别是抑制自噬，影响HSP 90客户蛋白水平，诱导细胞周期停滞，并抑制后期促进复合物/环体（APC/C）的酶活性。我们报道了所有这三种化合物都可以抑制自噬并导致HSP 90客户蛋白水平降低;然而，只有PES-Cl可以抑制APC/C并诱导G（2）/M停滞。这些差异的可能原因，以及这些原型化合物作为抗癌剂的进一步发展的影响，进行了讨论。
The chaperone HSP70 promotes the survival of cells exposed to many different types of stresses, and is also potently anti-apoptotic. The major stress-induced form of this protein, HSP70-1, is overexpressed in a number of human cancers, yet is negligibly expressed in normal cells. Silencing of the gene encoding HSP70-1 (HSPA1A) is cytotoxic to transformed but not normal cells. Therefore, HSP70 is considered to be a promising cancer drug target, and there has been active interest in the identification and characterization of HSP70 inhibitors for cancer therapy. Because HSP70 behaves in a relatively non-specific manner in the control of protein folding, to date there are no reliably-identified "clients" of this protein, nor is there consensus as to what the phenotypic effects of HSP70 inhibitors are on a cancer cell. Here for the first time we compare three recently-identified HSP70 inhibitors, PES-Cl, MKT-077, and Ver-155008, for their ability to impact some of the known and reported functions of this chaperone; specifically, the ability to inhibit autophagy, to influence the level of HSP90 client proteins, to induce cell cycle arrest, and to inhibit the enzymatic activity of the anaphase-promoting complex/cyclosome (APC/C). We report that all three of these compounds can inhibit autophagy and cause reduced levels of HSP90 client proteins; however, only PES-Cl can inhibit the APC/C and induce G(2)/M arrest. Possible reasons for these differences, and the implications for the further development of these prototype compounds as anti-cancer agents, are discussed.