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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 5

Mitochondrial SNPH supports tumor cell proliferation.

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Mitochondrial SNPH supports tumor cell proliferation.
(A) The indicated ...
(A) The indicated tumor cells transfected with control siRNA (Ctrl) or siRNA-SNPH were analyzed by direct cell counting (top) or cell viability by trypan blue exclusion (bottom) after 72 hours. The same number of cells were seeded at time 0. Data are expressed as mean ± SEM (n = 4). Red boxes indicate two cell types (C4-2B and MCF-7) with low to undetectable levels of endogenous SNPH. The statistical analyses per each cell type are as follows: BPH1, P = 0.03; A549, P = 0.004; H1299, NS; C4-2B, NS; DU145, P = 0.03; PC3, P = 0.002; LN229, P = 0.002; U251, P < 0.0001; U87, P = 0.03; MCF-7, NS; MDA-231, P = 0.01; Hs578T, P = 0.02 by 2-tailed Student’s t test. (B and C) PC3 cells transduced with pLKO or shRNA-SNPH (clones 0 and 5) were analyzed in a colony formation assay, and crystal violet–stained colonies (B) were counted after 10 days (C). Data are expressed as mean ± SEM (n = 3). ***P < 0.001 by ANOVA and Bonferroni’s post-test. (D) The indicated tumor cell types were transfected with vector or SNPH cDNA and analyzed by direct cell counting after 72 hours. Data are expressed as mean ± SD (n = 3). ***P < 0.0001, by 2-tailed Student’s t test. (E) PC3 cells transduced with pLKO or shRNA-SNPH were transfected with SOD2 cDNA and analyzed by direct cell counting. Data are expressed as mean ± SD (n = 3). *P < 0.01, by ANOVA and Bonferroni’s post test. (F) PC3 cells transduced with shRNA-SNPH were reconstituted with vector or SOD2 cDNA and analyzed by propidium iodide staining and flow cytometry. The cellular fractions in the indicated cell cycle phases are indicated. Data are expressed as mean ± SD (n = 3). **P = 0.01 by 2-tailed Student’s t test.
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