Millson Stefan H, Piper Peter W
Dept. of Molecular Biology and Biotechnology, University of Sheffield, Western Bank, Sheffield, United Kingdom.
Oncotarget. 2014 Jul 15;5(13):5054-64. doi: 10.18632/oncotarget.2077.
In human cells TORC1 mTOR (target of rapamycin) protein kinase complex renders heat shock transcription factor 1 (Hsf1) competent for stress activation. In such cells, as well as in yeast, the selective TORC1 inhibitor rapamycin blocks this activation in contrast to Hsp90 inhibitors which potently activate Hsf1. Potentially therefore rapamycin could prevent the Hsf1 activation that frequently compromises the efficiency of Hsp90 inhibitor cancer drugs. Little synergy was found between the effects of rapamycin and the Hsp90 inhibitor radicicol on yeast growth. However certain rapamycin resistance mutations sensitised yeast to Hsp90 inhibitor treatment and an Hsp90 mutation that overactivates Hsf1 sensitised cells to rapamycin. Rapamycin inhibition of the yeast Hsf1 was abolished by this Hsp90 mutation, as well as with the loss of Ppt1, the Hsp90-interacting protein phosphatase that is the ortholog of mammalian PP5. Unexpectedly Hsf1 activation was found to have a requirement for the rapamycin binding immunophilin FKBP12 even in the absence of rapamycin, while TORC1 "bypass" strains revealed that the rapamycin inhibition of yeast Hsf1 is not exerted through two of the major downstream targets of TORC1, the protein phosphatase regulator Tap42 and the protein kinase Sch9--the latter the ortholog of human S6 protein kinase 1.
A problem with most of the Hsp90 inhibitor drugs now in cancer clinic trials is that they potently activate Hsf1. This leads to an induction of heat shock proteins, many of which have a "pro-survival" role in that they help to protect cells from apopotosis. As the activation of Hsf1 requires TORC1, inhibitors of mTOR kinase could potentially block this activation of Hsf1 and be of value when used in combination drug therapies with Hsp90 inhibitors. However many of the mechanistic details of the TORC1 regulation of Hsf1, as well as the interplay between cellular resistances to rapamycin and to Hsp90 inhibitors, still remain to be resolved.
在人类细胞中，雷帕霉素靶蛋白（TORC1）的mTOR（雷帕霉素靶蛋白）蛋白激酶复合物使热休克转录因子1（Hsf1）具备应激激活能力。在这类细胞以及酵母细胞中，选择性TORC1抑制剂雷帕霉素会阻断这种激活，与之形成对比的是，Hsp90抑制剂能有效激活Hsf1。因此，雷帕霉素有可能预防Hsf1的激活，而这种激活常常会损害Hsp90抑制剂类抗癌药物的疗效。雷帕霉素与Hsp90抑制剂萝卜硫素对酵母生长的影响之间几乎没有协同作用。然而，某些雷帕霉素抗性突变会使酵母对Hsp90抑制剂治疗敏感，而一个过度激活Hsf1的Hsp90突变会使细胞对雷帕霉素敏感。雷帕霉素对酵母Hsf1的抑制作用会因这种Hsp90突变而消除，同时也会因与Hsp90相互作用的蛋白磷酸酶Ppt1（哺乳动物PP5的直系同源物）的缺失而消除。出乎意料的是，即使在没有雷帕霉素的情况下，也发现Hsf1的激活需要雷帕霉素结合免疫亲和蛋白FKBP12，而TORC1“旁路”菌株表明，雷帕霉素对酵母Hsf1的抑制作用并非通过TORC1的两个主要下游靶点——蛋白磷酸酶调节因子Tap42和蛋白激酶Sch9（后者是人类S6蛋白激酶1的直系同源物）来发挥作用。
目前大多数处于癌症临床试验阶段的Hsp90抑制剂药物存在一个问题，即它们能有效激活Hsf1。这会导致热休克蛋白的诱导，其中许多热休克蛋白具有“促生存”作用，因为它们有助于保护细胞免受凋亡。由于Hsf1的激活需要TORC1，mTOR激酶抑制剂有可能阻断Hsf1的这种激活，在与Hsp90抑制剂联合用药治疗时可能具有价值。然而，TORC1对Hsf1调控的许多机制细节，以及细胞对雷帕霉素和Hsp90抑制剂抗性之间的相互作用，仍有待解决。
