VCP 重新定位限制了 PC3 前列腺癌细胞饥饿期间的线粒体活性、GSH 消耗和铁死亡,Genes to Cells

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VCP 重新定位限制了 PC3 前列腺癌细胞饥饿期间的线粒体活性、GSH 消耗和铁死亡
Genes to Cells ( IF 1.3 ) Pub Date : 2021-05-25 , DOI: 10.1111/gtc.12872
Promise Ogor ₁ , Tomoki Yoshida ₁ , Masaaki Koike ₁ , Akira Kakizuka ₁

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在危机时期，细胞必须补偿才能生存。为此，细胞可能需要改变关键蛋白质的亚细胞定位。在这里，我们表明在饥饿期间，最丰富的可溶性 ATP 酶 VCP 在 PC3 前列腺癌细胞的核周区域重新定位并形成聚集体样结构。这种运动与代谢状态降低有关，其中线粒体活性和 ROS 产生减少。VCP 似乎明确地感知谷氨酰胺水平，因为从完全培养基中去除谷氨酰胺会触发 VCP 重新定位，并将其添加到饥饿培养基中会减弱 VCP 重新定位。在 Gln(+) 饥饿培养基中培养的细胞在细胞质中表现出均匀分布的 VCP（游离 VCP）并经历铁死亡细胞死亡，这与 GSH 水平降低有关。而且，在饥饿培养基中添加 VCP 抑制剂 CB-5083 可阻止 VCP 重新定位并引发铁死亡细胞死亡。同样，与 ATP 酶活性无关的 GFP 融合 VCP 蛋白的表达显示出游离 VCP 并在饥饿期间引发细胞死亡。这些结果表明游离 VCP 对维持线粒体功能至关重要，PC3 细胞采用 VCP 自聚集策略来抑制线粒体活性，以逃避饥饿期间的细胞死亡，这是一种新的 VCP 介导的生存机制。

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VCP relocalization limits mitochondrial activity, GSH depletion and ferroptosis during starvation in PC3 prostate cancer cells

During periods of crisis, cells must compensate to survive. To this end, cells may need to alter the subcellular localization of crucial proteins. Here, we show that during starvation, VCP, the most abundant soluble ATPase, relocalizes and forms aggregate-like structures at perinuclear regions in PC3 prostate cancer cells. This movement is associated with a lowered metabolic state, in which mitochondrial activity and ROS production are reduced. VCP appears to explicitly sense glutamine levels, as removal of glutamine from complete medium triggered VCP relocalization and its addition to starvation media blunted VCP relocalization. Cells cultured in Gln(+) starvation media exhibited uniformly distributed VCP in the cytoplasm (free VCP) and underwent ferroptotic cell death, which was associated with a decrease in GSH levels. Moreover, the addition of a VCP inhibitor, CB-5083, in starvation media prevented VCP relocalization and triggered ferroptotic cell death. Likewise, expression of GFP-fused VCP proteins, irrespective of ATPase activities, displayed free VCP and triggered cell death during starvation. These results indicate that free VCP is essential for the maintenance of mitochondrial function and that PC3 cells employ a strategy of VCP self-aggregation to suppress mitochondrial activity in order to escape cell death during starvation, a novel VCP-mediated survival mechanism.

更新日期：2021-05-25

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