Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
J Clin Invest. 2013 Jul;123(7):2907-20. doi: 10.1172/JCI67841. Epub 2013 Jun 10.
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.
代谢重编程是肿瘤进展的重要驱动因素；然而，肿瘤细胞迁移和转移的代谢调节剂尚不清楚。在这里，我们表明肿瘤通过定位于线粒体中的 HSP90 伴侣的功能在营养剥夺下维持能量产生。使用癌细胞系，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），抑制营养感应 AMPK 的激活及其底物 UNC-51 样激酶（ULK1），维持细胞骨架动力学，并释放细胞迁移效应因子粘着斑激酶（FAK）免受自噬起始因子 FIP200 的抑制。反过来，这导致在低营养条件下增强肿瘤细胞侵袭，并在小鼠疾病模型中向骨骼或肝脏转移扩散。此外，我们发现磷酸化 ULK1 水平与非小细胞肺癌患者总生存期缩短相关。这些结果表明，包括 TRAP-1 在内的线粒体 HSP90 伴侣通过限制营养传感器 AMPK 的激活和防止自噬来克服代谢应激并促进肿瘤细胞转移。
