Proteotoxic stress targeted therapy (PSTT): induction of protein misfolding enhances the antitumor effect of the proteasome inhibitor bortezomib.
Proteotoxic stress targeted therapy (PSTT): induction of protein misfolding enhances the antitumor effect of the proteasome inhibitor bortezomib.
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DOI：
10.18632/oncotarget.246
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发表时间：
2011-03
期刊：
影响因子：
--
通讯作者：
Gudkov AV
中科院分区：
文献类型：
--
作者：
Neznanov N;Komarov AP;Neznanova L;Stanhope-Baker P;Gudkov AV
蛋白毒性应激（PS）在涉及错误折叠蛋白质积累的多种条件下在细胞中产生。为了避免未缓解的PS的毒性，细胞激活热休克反应（HSR）。HSR涉及诸如泛素和非持家分子伴侣Hsp 70等因子的上调，这些因子有助于异常蛋白质的代谢。PS-HSR轴是潜在的抗癌治疗靶点，因为许多肿瘤细胞由于其快速增殖和翻译而显示出组成性PS和对HSR的依赖性。事实上，通过刺激蛋白质错误折叠（高热）、抑制蛋白酶体（硼替佐米）或抑制Hsp 90（格尔德霉素）诱导PS都已被考虑或用于癌症治疗。我们发现硼替佐米与蛋白质错误折叠诱导剂（高热或嘌呤霉素）的组合导致PS增强。HSR也被诱导，但不能减轻升高的PS和细胞死亡，主要通过p53非依赖性凋亡。因此，联合治疗在体外比组分单一治疗更具细胞毒性。与此一致，在多发性骨髓瘤小鼠模型中，无毒剂量的嘌呤霉素与硼替佐米联合用药显著增加了硼替佐米的抗肿瘤活性。这些结果为使用破坏PS和HSR平衡的组合治疗来增加抗癌疗法的治疗指数提供了支持。
Proteotoxic stress (PS) is generated in cells under a variety of conditions involving accumulation of misfolded proteins. To avoid the toxicity of unmitigated PS, cells activate the heat shock response (HSR). HSR involves upregulation of factors such as ubiquitin and the non-housekeeping chaperone Hsp70 which assist with metabolism of aberrant proteins. The PS-HSR axis is a potential anticancer treatment target since many tumor cells display constitutive PS and dependence on HSR due to their rapid rates of proliferation and translation. In fact, induction of PS via stimulation of protein misfolding (hyperthermia), inhibition of proteasomes (bortezomib) or inhibition of Hsp90 (geldanamycin) have all been considered or used for cancer treatment. We found that combination of bortezomib with an inducer of protein misfolding (hyperthermia or puromycin) resulted in enhanced PS. HSR was also induced, but could not mitigate the elevated PS and the cells died via largely p53-independent apoptosis. Thus, combination treatments were more cytotoxic in vitro than the component single treatments. Consistent with this, combination of non-toxic doses of puromycin with bortezomib significantly increased the antitumor activity of bortezomib in a mouse model of multiple myeloma. These results provide support for using combination treatments that disrupt the balance of PS and HSR to increase the therapeutic index of anticancer therapies.
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