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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 2

SNPH regulation of mitochondrial bioenergetics.

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SNPH regulation of mitochondrial bioenergetics.
(A and B) PC3 cells stab...
(A and B) PC3 cells stably transduced with control pLKO or shRNA-SNPH (clone 0 or 5) were analyzed for OCR (A) or ATP production (B). Data are expressed as mean ± SD of replicates of a representative experiment (n = 3). ***P < 0.0001, by 2-tailed Student’s t test (A). ***P < 0.001 by ANOVA and Bonferroni’s post-test (B). (C and D) PC3 cells transfected with control siRNA (Ctrl) or siRNA-SNPH were transduced with control adenovirus (Ad-LacZ) or SNPH-directed adenovirus (Ad-SNPH), and analyzed for OCR (C) or ATP production (D). Data are expressed as mean ± SD of replicates of a representative experiment (n = 3). ***P < 0.001 by ANOVA and Bonferroni’s post-test. (E and F) PC3 cells transduced with pLKO or shRNA-SNPH were analyzed for oxidative phosphorylation complex II (C.II) activity (E) and normalized to citrate synthase activity (F). Gray tracing, blank reaction. Data are expressed as mean ± SD of replicates of a representative experiment (n = 3). **P < 0.01 by ANOVA and Bonferroni’s post-test. (G and H) The experimental conditions were as in E and F, except that transduced PC3 cells were analyzed for oxidative phosphorylation complex I (C.I) activity (G) and normalized to citrate synthase activity (H). Gray tracing, blank reaction. Data are expressed as mean ± SD of replicates of a representative experiment (n = 3). NS, not significant (P > 0.05) by ANOVA and Bonferroni’s post-test. (I) PC3 cells transduced with pLKO or shRNA-SNPH were treated with CHX, and aliquots of cell extracts harvested at the indicated time intervals after release (h) were analyzed by Western blotting. (J and K) Protein bands from the experiment in I were quantified by densitometric scanning after CHX release. Changes in SDHA (J) or SDHB (K) protein bands in pLKO or shRNA-SNPH are shown. Data are expressed as mean ± SD (n = 4). The statistical analyses are as follows: SDHA (J), 2 hours, P = 0.05; 4 hours, P < 0.0001; 6 hours, P = 0.0001; 8 hours, P = 0.0001; 10 hours, P < 0.0001; SDHB (K), 2 hours, P = 0.14; 4 hours, P = 0.0007; 6 hours, P < 0.0001; 8 hours, P < 0.0001; 10 hours, P < 0.0001, by 2-tailed Student’s t test.
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