Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
Syntaphilin controls a mitochondrial rheostat for proliferation-motility decisions in cancer
M. Cecilia Caino, … , Lucia R. Languino, Dario C. Altieri
M. Cecilia Caino, … , Lucia R. Languino, Dario C. Altieri
Published September 11, 2017
Citation Information: J Clin Invest. 2017;127(10):3755-3769. https://doi.org/10.1172/JCI93172.
View: Text | PDF
Research Article Cell biology Oncology

Syntaphilin controls a mitochondrial rheostat for proliferation-motility decisions in cancer

  • Text
  • PDF
Abstract

Tumors adapt to an unfavorable microenvironment by controlling the balance between cell proliferation and cell motility, but the regulators of this process are largely unknown. Here, we show that an alternatively spliced isoform of syntaphilin (SNPH), a cytoskeletal regulator of mitochondrial movements in neurons, is directed to mitochondria of tumor cells. Mitochondrial SNPH buffers oxidative stress and maintains complex II–dependent bioenergetics, sustaining local tumor growth while restricting mitochondrial redistribution to the cortical cytoskeleton and tumor cell motility. Conversely, introduction of stress stimuli to the microenvironment, including hypoxia, acutely lowered SNPH levels, resulting in bioenergetics defects and increased superoxide production. In turn, this suppressed tumor cell proliferation but increased tumor cell invasion via greater mitochondrial trafficking to the cortical cytoskeleton. Loss of SNPH or expression of an SNPH mutant lacking the mitochondrial localization sequence resulted in increased metastatic dissemination in xenograft or syngeneic tumor models in vivo. Accordingly, tumor cells that acquired the ability to metastasize in vivo constitutively downregulated SNPH and exhibited higher oxidative stress, reduced cell proliferation, and increased cell motility. Therefore, SNPH is a stress-regulated mitochondrial switch of the cell proliferation-motility balance in cancer, and its pathway may represent a therapeutic target.

Authors

M. Cecilia Caino, Jae Ho Seo, Yuan Wang, Dayana B. Rivadeneira, Dmitry I. Gabrilovich, Eui Tae Kim, Ashani T. Weeraratna, Lucia R. Languino, Dario C. Altieri

×

Figure 4

SNPH regulation of mitochondrial oxidative stress controls tumor cell motility.

Options: View larger image (or click on image) Download as PowerPoint
SNPH regulation of mitochondrial oxidative stress controls tumor cell mo...
(A) LN229 cells were transfected with vector or Flag-SNPH cDNA and analyzed for subcellular mitochondrial localization by confocal fluorescence microscopy. Three-dimensional isosurface renderings of representative cells are shown. (B) LN229 cells transfected with control siRNA or siRNA-SNPH were treated with vehicle or MT (200 μM) and analyzed by fluorescence microscopy. Masks are superimposed to the mitochondrial fluorescence channel (MTC02) to indicate the cell border (cyan lines, based on the actin channel) and the cortical region (area between the cyan and magenta lines). Arrowheads, cortical mitochondria. Scale bar: 10 μm. (C–E) LN229 cells transfected with siRNA-SNPH were transfected with vector, SOD2, or Prx3 cDNA and analyzed for cell motility in a 2D chemotaxis chamber (C), with quantification of speed of cell migration (D) and distance traveled by individual cells (E). Each tracing in C and symbol in E corresponds to an individual cell. Data are expressed as mean ± SEM (n = 91–112). ***P < 0.0001, by ANOVA and Bonferroni’s post-test. The cutoff velocities for each condition in 2D chemotaxis experiments (C) are indicated.
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts