Resveratrol activates autophagic cell death in prostate cancer cells via downregulation of STIM1 and the mTOR pathway.
Resveratrol activates autophagic cell death in prostate cancer cells via downregulation of STIM1 and the mTOR pathway.
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DOI：
10.1002/mc.22324
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发表时间：
2016-05
影响因子：
4.6
通讯作者：
Singh BB
中科院分区：
文献类型：
--
作者：
Selvaraj S;Sun Y;Sukumaran P;Singh BB
白藜芦醇（RSV）是一种天然多酚，被认为可以诱导细胞周期停滞并激活包括前列腺癌在内的多种癌细胞中细胞凋亡介导的细胞死亡。然而，已经提出了几种分子机制的化学预防作用，RSV发挥其抗增殖作用的雄激素非依赖性前列腺癌细胞的确切机制仍然存在疑问。在本研究中，我们发现RSV激活PC 3和DU 145细胞中的自噬性细胞死亡，这依赖于基质相互作用分子1（STIM 1）的表达。RSV治疗以时间依赖性方式降低STIM 1表达，并减弱STIM 1与TRPC 1和Orai 1的相关性。此外，RSV治疗还减少ER钙储存和钙储存操纵的钙进入（SOCE），其诱导内质网（ER）应激，从而激活AMPK并抑制AKT/mTOR途径。同样，SKF-96365抑制SOCE可降低PC 3和DU 145细胞的存活和增殖，抑制AKT/mTOR通路并诱导自噬细胞死亡。重要的是，由RSV引起的SOCE抑制和随后的自噬细胞死亡被STIM 1过表达逆转。STIM 1过表达可恢复PC 3细胞的SOCE，防止mTOR磷酸化的丧失，降低CHOP和LC 3A的表达。综上所述，我们的研究结果首次揭示了RSV通过调节SOCE机制诱导PC 3和DU 145细胞中自噬介导的细胞死亡，包括下调STIM 1表达和通过消耗ER钙库触发ER应激。
Resveratrol (RSV), a natural polyphenols, has been suggested to induce cell cycle arrest and activate apoptosis-mediated cell death in several cancer cells, including prostate cancer. However, several molecular mechanisms have been proposed on its chemopreventive action, the precise mechanisms by which RSV exerts its anti-proliferative effect in androgen-independent prostate cancer cells remain questionable. In the present study, we show that RSV activates autophagic cell death in PC3 and DU145 cells, which was dependent on stromal interaction molecule 1 (STIM1) expression. RSV treatment decreases STIM1 expression in a time dependent manner and attenuates STIM1 association with TRPC1 and Orai1. Furthermore, RSV treatment also decreases ER calcium storage and store operated calcium entry (SOCE), which induces endoplasmic reticulum (ER) stress thereby activating AMPK and inhibiting the AKT/mTOR pathway. Similarly, inhibition of SOCE by SKF-96365 decreases the survival and proliferation of PC3 and DU145 cells and inhibits AKT/mTOR pathway and induces autophagic cell death. Importantly, SOCE inhibition and subsequent autophagic cell death caused by RSV was reversed by STIM1 overexpression. STIM1 overexpression restored SOCE, prevent the loss of mTOR phosphorylation and decreased the expression of CHOP and LC3A in PC3 cells. Taken together, for the first time, our results revealed that RSV induces autophagy mediated cell death in PC3 and DU145 cells through regulation of SOCE mechanisms, including down regulating STIM1 expression and trigger ER stress by depleting ER calcium pool.