Journal article
Metabolic stress regulates cytoskeletal dynamics and metastasis of cancer cells
The Journal of clinical investigation, v 123(7), pp 2907-2920
01 Jul 2013
PMID: 23921130
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
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Details
- Title
- Metabolic stress regulates cytoskeletal dynamics and metastasis of cancer cells
- Creators
- M. Cecilia Caino - Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, Pennsylvania, USAYoung Chan Chae - Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, Pennsylvania, USAValentina Vaira - Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, Pennsylvania, USAStefano Ferrero - Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, Pennsylvania, USAMario Nosotti - Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, Pennsylvania, USANina M Martin - Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, Pennsylvania, USAAshani Weeraratna - Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, Pennsylvania, USAMichael O’Connell - Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, Pennsylvania, USADanielle Jernigan - Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, Pennsylvania, USAAlessandro Fatatis - Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, Pennsylvania, USALucia R Languino - Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, Pennsylvania, USASilvano Bosari - Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, Pennsylvania, USADario C Altieri - Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, Pennsylvania, USA
- Publication Details
- The Journal of clinical investigation, v 123(7), pp 2907-2920
- Publisher
- American Society for Clinical Investigation
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000321316700019
- Scopus ID
- 2-s2.0-84879653531
- Other Identifier
- 991014878211204721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Medicine, Research & Experimental