Metabolic stress regulates cytoskeletal dynamics and metastasis of cancer cells
Metabolic stress regulates cytoskeletal dynamics and metastasis of cancer cells
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DOI：
10.1172/jci67841
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发表时间：
2013-07-01
影响因子：
15.9
通讯作者：
Altieri, Dario C.
中科院分区：
文献类型：
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作者：
Caino, M. Cecilia;Chae, Young Chan;Altieri, Dario C.
代谢重编程是肿瘤进展的重要驱动力；然而，对肿瘤细胞运动和转移的代谢调节尚不清楚。在这里，我们表明，肿瘤在营养缺乏的情况下，通过线粒体中划分的HSP90伴侣的功能来维持能量生产。利用癌细胞系，我们发现线粒体HSP90蛋白，包括肿瘤坏死因子受体相关蛋白-1(TRAP-1)，抑制了营养感知AMPK及其底物UNC-51样激酶(ULK1)的激活，保持了细胞骨架的动力学，并释放了细胞运动效应因子粘着斑激酶(FAK)，使其免受自噬启动剂FIP200的抑制。反过来，在小鼠的疾病模型中，这会导致肿瘤细胞在低营养条件下侵袭增强，并转移到骨骼或肝脏。此外，我们发现，在非小细胞肺癌患者中，磷酸化的ULK1水平与总生存期缩短相关。这些结果表明，包括TRAP-1在内的线粒体HSP90伴侣通过限制营养感受器AMPK的激活和防止自噬来克服代谢应激，促进肿瘤细胞的转移。
Metabolic reprogramming is an important driver of tumor progression; however, the metabolic regulators of tumor cell motility and metastasis are not understood. Here, we show that tumors maintain energy production under nutrient deprivation through the function of HSP90 chaperones compartmentalized in mitochondria. Using cancer cell lines, we found that mitochondrial HSP90 proteins, including tumor necrosis factor receptor-associated protein-1 (TRAP-1), dampen the activation of the nutrient-sensing AMPK and its substrate UNC-51-like kinase (ULK1), preserve cytoskeletal dynamics, and release the cell motility effector focal adhesion kinase (FAK) from inhibition by the autophagy initiator FIP200. In turn, this results in enhanced tumor cell invasion in low nutrients and metastatic dissemination to bone or liver in disease models in mice. Moreover, we found that phosphorylated ULK1 levels were correlated with shortened overall survival in patients with non-small cell lung cancer. These results demonstrate that mitochondrial HSP90 chaperones, including TRAP-1, overcome metabolic stress and promote tumor cell metastasis by limiting the activation of the nutrient sensor AMPK and preventing autophagy.