Facilitating Akt Clearance via Manipulation of Hsp70 Activity and Levels
Facilitating Akt Clearance via Manipulation of Hsp70 Activity and Levels
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DOI：
10.1074/jbc.m109.057208
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发表时间：
2010-01-22
影响因子：
4.8
通讯作者：
Dickey, Chad A.
中科院分区：
文献类型：
--
作者：
Koren, John, III;Jinwal, Umesh K.;Dickey, Chad A.
70-kDa热休克家族的成员可以控制和操纵一系列致癌客户蛋白。Hsp 70在这些客户蛋白的折叠和降解中的作用使其成为某些癌症的潜在药物靶标。吩噻嗪家族的化合物，以及类黄酮杨梅素，最近被证明抑制Hsp 70-ATP酶活性，而二氢嘧啶家族的成员刺激ATP酶功能。Akt是一种主要的存活激酶，被发现受到Hsp 70的调节，并且当这些化合物增加或降低Hsp 70的ATP酶活性时，Akt水平也增加或降低。此外，增加热休克蛋白70水平的同时抑制其ATP酶功能协同降低Akt水平在更大程度上比单独操纵，提供了新的见解客户的命运决定。当用小干扰RNA沉默Hsp 70表达时，Hsp 70抑制剂介导的Akt减少被阻止。抑制Hsp 70 ATP酶功能仅在先前显示Akt功能障碍的乳腺癌细胞系中产生细胞毒性事件，表明治疗特异性取决于Hsp 70客户端概况。因此，增加Hsp 70水平结合抑制其ATP酶功能可能有助于显著降低Akt水平并促进某些类型癌症中的细胞死亡。
Members of the 70-kDa heat shock family can control and manipulate a host of oncogenic client proteins. This role of Hsp70 in both the folding and degradation of these client proteins makes it a potential drug target for certain forms of cancer. The phenothiazine family of compounds, as well as the flavonoid myricetin, was recently shown to inhibit Hsp70-ATPase activity, whereas members of the dihydropyrimidine family stimulated ATPase function. Akt, a major survival kinase, was found to be under the regulation of Hsp70, and when the ATPase activity of Hsp70 was increased or decreased by these compounds, Akt levels were also increased or decreased. Also, increasing Hsp70 levels concurrent with inhibition of its ATPase function synergistically reduced Akt levels to a greater extent than either manipulation alone, providing new insights about client fate decisions. Akt reductions mediated by Hsp70 inhibitors were prevented when Hsp70 expression was silenced with small interfering RNA. Inhibiting Hsp70 ATPase function produced cytotoxic events only in breast cancer cell lines where Akt dysfunction was previously shown, suggesting therapeutic specificity depending on the Hsp70 client profile. Thus, increasing Hsp70 levels combined with inhibiting its ATPase function may serve to dramatically reduce Akt levels and facilitate cell death in certain types of cancer.