Involvement of Stat3 phosphorylation in mild heat shock-induced thermotolerance
Involvement of Stat3 phosphorylation in mild heat shock-induced thermotolerance
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DOI：
10.1016/j.yexcr.2019.02.011
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发表时间：
2019-04-15
影响因子：
3.7
通讯作者：
Nakayama, Yuji
中科院分区：
文献类型：
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作者：
Matozaki, Masashi;Saito, Youhei;Nakayama, Yuji
热耐受性是细胞通过预先暴露于热休克而变得对应激具有抗性的现象，并且其发展与热休克蛋白（Hsps）（包括Hsp 70）的诱导有关。我们以前的研究表明，热休克蛋白70的表达受细胞因子信号转录因子Stat 3的调控，但Stat 3在热耐受中的作用尚不清楚。在这项研究中，我们研究了Stat 3在获得耐热性的可能参与。我们发现，严重的热休克诱导的形态学变化和细胞活力的降低，这是抑制暴露于非致命的轻度热休克严重热休克之前。这种热耐受性的发展伴随着Stat 3磷酸化和lisps如Hsp 105，Hsp 70和11 sp27的诱导。JAK酪氨酸激酶抑制剂AG 490可抑制Stat 3磷酸化和Hsp诱导。与此一致，我们发现，轻度热休克诱导的耐热性部分抑制AG 490或敲低的Hsp 105。我们还发现Stat 3抑制剂Stattic通过抑制轻度热休克诱导的Stat 3磷酸化和Hsp 105表达来抑制热耐受的获得。这些结果表明，温和的热休克依赖性的JAK-Stat信号通路的刺激有助于通过诱导包括Hsp 105的lisps的热耐受性的发展。该信号通路可能是热疗癌症治疗的有用靶点。
Thermotolerance is a phenomenon in which cells become resistant to stress by prior exposure to heat shock, and its development is associated with the induction of heat shock proteins (Hsps), including Hsp70. We previously showed that the expression of Hsp70 is regulated by the cytokine signaling transcription factor Stat3, but the role of Stat3 in thermotolerance is not known. In this study, we examined the possible involvement of Stat3 in the acquisition of thermotolerance. We found that severe heat shock-induced morphological changes and decreases in cell viability, which were suppressed by exposure to non-lethal mild heat shock prior to severe heat shock. This thermotolerance development was accompanied by Stat3 phosphorylation and the induction of lisps such as Hsp105, Hsp70, and 11sp27. Stat3 phosphorylation and Hsp induction were inhibited by AG490, an inhibitor of JAK tyrosine kinase. Consistent with this, we found that mild heat shock-induced thermotolerance was partially suppressed by AG490 or knockdown of Hsp105. We also found that the Stat3 inhibitor Stattic suppresses the acquisition of thermotolerance by inhibiting the mild heat shock-induced Stat3 phosphorylation and Hsp105 expression. These results suggest that the mild heat shock-dependent stimulation of the JAK-Stat signaling pathway contributes to the development of thermotolerance via the induction of lisps including Hsp105. This signaling pathway may be a useful target for hyperthermia cancer therapy.