Metabolic stress regulates cytoskeletal dynamics and metastasis of cancer cells
M. Cecilia Caino, … , Silvano Bosari, Dario C. Altieri
M. Cecilia Caino, … , Silvano Bosari, Dario C. Altieri
Published June 10, 2013
Citation Information: J Clin Invest. 2013;123(7):2907-2920. https://doi.org/10.1172/JCI67841.
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Research Article Oncology

Metabolic stress regulates cytoskeletal dynamics and metastasis of cancer cells

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.

Authors

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

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Figure 1

Gamitrinib inhibition of tumor cell motility.

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Gamitrinib inhibition of tumor cell motility. (A and B) Gamitrinib-treat...
(A and B) Gamitrinib-treated (Gam) (5 μM) PC3 cells were analyzed for cell migration (A) or invasion (B). Mean ± SEM (n = 3), ***P < 0.0001. (C and D) 3D organotypic LN229 spheroids treated with vehicle or Gamitrinib (1.25–2.5 μM) were analyzed by phase contrast microscopy (C, top), and mask-inverted images (C, bottom) were used to quantify the length and area between the core and the invasive cores (D). Mean ± SEM (n = 3), *P = 0.0171–0.0295; ***P < 0.0001. Original magnification, ×20 (A and B); ×4 (C). (E) PC3 cells were treated with vehicle or Gamitrinib as in A and B and analyzed for cell proliferation by direct cell counting. Mean ± SEM (n = 3). (F) LN229 spheroids were stained with calcein-AM (live cells, green) and Topro-3 (dead cells, blue) and analyzed by 2-photon microscopy. Original magnification, ×20. (G) PC3 cells were treated with vehicle or Gamitrinib (5 μM) and analyzed in a wound-closure assay after 16 or 24 hours. Representative micrographs (top) and quantification of cell motility (bottom) are shown. The leading front of cell migration is indicated by dotted lines. Mean ± SEM (n = 3), ***P < 0.0001–0.0004. Original magnification, ×5. (H) The experimental conditions are the same as in G except that normal human MRC-5 lung fibroblasts treated with vehicle or 2 concentrations of Gamitrinib (5–10 μM) were analyzed in a wound-closure assay after 16 or 24 hours. Original magnification, ×10.