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
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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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 3

Cellular requirements of mitochondrial Hsp90-directed tumor cell migration.

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Cellular requirements of mitochondrial Hsp90-directed tumor cell migrati...
(A) Representative images from video sequences of FBS-stimulated PC3 cells treated with vehicle or Gamitrinib (5 μM) and analyzed by real-time quantification of membrane ruffling (lamellipodia growth and retraction) by stroboscopic imaging. Scale bars: 16.2 μm length. (B) Stroboscopic images representing an area of analysis (white line in A) for the indicated time intervals. (C) Quantification of membrane ruffling frequency. Each bar corresponds to an individual cell. Broken lines, average values. (D) Average ruffling frequency (top), and quantification of speed of lamellipodia retraction in μm/min (bottom). Mean ± SEM (n = 15). ***P < 0.0001. (E and F) Tumor cells treated with (+) or without (–) Gamitrinib (5 μM) were analyzed by Western blotting. p, phosphorylated. (G) Serum-starved A549 cells were stimulated with EGF (100 ng/ml, 2 minutes) or FBS (10%, 5 minutes), treated with (+) or without (–) Gamitrinib (5 μM), and analyzed for GTP-bound Rac1 or Cdc42. (H) PC3 cells were transfected with vector or cDNA encoding FAK and analyzed by Western blotting. p, phosphorylated. (I and J), PC3 cells transfected as in (H) and treated with (+) or without (–) Gamitrinib (5 μM) were analyzed for cell migration (left) or invasion (right) (I), or cell proliferation (J). Mean ± SEM (n = 3), ***P < 0.0001. (K and L) PC3 cells were transfected with vector or cDNAs encoding Src (K) or constitutively active Cdc42V12 mutant (L) and analyzed by Western blotting (left) or cell migration (right) in the presence (+) or absence (–) of Gamitrinib. Mean ± SEM (n = 3). **P = 0.0094.