Metabolic stress regulates cytoskeletal dynamics and metastasis of cancer cells

M. Cecilia Caino, Young Chan Chae, Valentina Vaira, Stefano Ferrero, Mario Nosotti, Nina M. Martin, Ashani Weeraratna, Michael O'Connell, Danielle Jernigan, Alessandro Fatatis, Lucia R. Languino, Silvano Bosari, Dario C. Altieri

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)2907-2920
Number of pages14
JournalJournal of Clinical Investigation
Volume123
Issue number7
DOIs
Publication statusPublished - Jul 1 2013

ASJC Scopus subject areas

  • Medicine(all)

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  • Cite this

    Caino, M. C., Chae, Y. C., Vaira, V., Ferrero, S., Nosotti, M., Martin, N. M., Weeraratna, A., O'Connell, M., Jernigan, D., Fatatis, A., Languino, L. R., Bosari, S., & Altieri, D. C. (2013). Metabolic stress regulates cytoskeletal dynamics and metastasis of cancer cells. Journal of Clinical Investigation, 123(7), 2907-2920. https://doi.org/10.1172/JCI67841