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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adenylate Kinase / metabolism
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Animals
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Antineoplastic Agents / pharmacology
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Autophagy-Related Protein-1 Homolog
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Bone Neoplasms / metabolism*
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Bone Neoplasms / secondary
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Carcinoma, Non-Small-Cell Lung / metabolism*
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Carcinoma, Non-Small-Cell Lung / mortality
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Carcinoma, Non-Small-Cell Lung / secondary
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Cell Line, Tumor
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Cell Movement
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Cytoskeleton / metabolism*
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Female
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Gene Knockdown Techniques
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Guanidines / pharmacology
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HSP90 Heat-Shock Proteins / genetics
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HSP90 Heat-Shock Proteins / metabolism
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Hexokinase / metabolism
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Kaplan-Meier Estimate
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Lactams, Macrocyclic / pharmacology
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Liver Neoplasms, Experimental / metabolism*
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Liver Neoplasms, Experimental / secondary
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Lung Neoplasms / metabolism*
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Lung Neoplasms / mortality
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Lung Neoplasms / pathology
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Mice
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Mice, SCID
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Mitochondria / metabolism
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Mitochondrial Membranes / enzymology
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NIH 3T3 Cells
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Neoplasm Transplantation
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Phosphorylation
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Protein Processing, Post-Translational
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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RNA, Small Interfering / genetics
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Stress, Physiological*
Substances
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Antineoplastic Agents
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Guanidines
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HSP90 Heat-Shock Proteins
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Intracellular Signaling Peptides and Proteins
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Lactams, Macrocyclic
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RNA, Small Interfering
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TRAP1 protein, human
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gamitrinib-G4
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Hexokinase
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Autophagy-Related Protein-1 Homolog
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Protein Serine-Threonine Kinases
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ULK1 protein, human
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Adenylate Kinase