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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.
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Research Article Cell biology Oncology

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

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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

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Figure 8

Hypoxic and oxidative stress regulation of SNPH.

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Hypoxic and oxidative stress regulation of SNPH.
(A) PC3 cells were expo...
(A) PC3 cells were exposed to normoxia (N) or hypoxia (H; 1% O2 for 24 hours) and analyzed by Western blotting. (B) Cases of clear cell renal cell carcinoma in the TCGA database were stratified for SNPH mRNA expression and VHL mutational status. Mut, mutations; Trunc, truncated; del, deletions. Each symbol corresponds to an individual tumor. **P < 0.01; ***P < 0.001 by ANOVA and Bonferroni’s post-test. (C and D) LN229 cells exposed to normoxia or hypoxia as in A were analyzed for mitochondrial trafficking to the cortical cytoskeleton by fluorescence microscopy (C), and cortical mitochondria (mito) were quantified (D). Each symbol corresponds to an individual cell. ***P < 0.0001, by 2-tailed Student’s t test. The representative images displayed in C are brightness- and contrast-enhanced to highlight cortical mitochondria. Quantification was done in unsaturated images. (E and F) PC3 cells were treated with the indicated concentrations of DMNQ and analyzed by Western blotting (E) or qPCR amplification of SNPH mRNA (F). Data are expressed as mean ± SD (n = 3). ***P < 0.001, by ANOVA and Bonferroni’s post-test. (G and H) Normal diploid HFFs or normal human prostate epithelial cells (RWPE1) were transfected with control siRNA or siRNA-SNPH and analyzed for OCR (G) or ATP production (H). Data are mean ± SD (HFFs, n = 3; RWPE1, n = 12). *P = 0.001 to P < 0.0001; NS, not significant, by 2-tailed Student’s t test. (I) HFFs (top) or RWPE1 cells (bottom) transfected as in G were analyzed for cell motility in a 2D chemotaxis chamber. Each trace corresponds to the movements of an individual cell. (J and K) HFFs or RWPE1 cells transfected as in G were analyzed by 2D chemotaxis, and speed of cell migration (J) and distance traveled by individual cells (G) were quantified. Data are expressed as mean ± SD (HFFs, n = 35–42; RWPE1 cells, n = 50–52). NS, 2-tailed Student’s t test.
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