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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 3

Effect of SNPH on mitochondrial oxidative stress.

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Effect of SNPH on mitochondrial oxidative stress.
(A) LN229 cells expres...
(A) LN229 cells expressing control siRNA (Ctrl) or siRNA-SNPH were transfected with cDNA encoding antioxidant SOD2 or Prx3 and analyzed for total ROS production by fluorescence microscopy. Data are expressed as mean ± SD of single-cell determinations (Ctrl, n = 109; SNPH, n = 75; SOD2, n = 74; and Prx3, n = 55). **P < 0.01 by ANOVA and Bonferroni’s post-test. CellROX, ROS sensor. (B) PC3 cells transduced with pLKO or shRNA-SNPH (clones 0 and 5) were analyzed for mitochondrial superoxide production (mitoSOX) by fluorescence microscopy. Data are expressed as mean ± SD of single cell determinations (pLKO, n = 202; SNPH #0, n = 296; SNPH #5, n = 297). ***P < 0.001 by ANOVA and Bonferroni’s post-test. FU, fluorescence units. (C) PC3 shRNA-SNPH #0 cells were analyzed for NAD+/NADH ratio. Data are expressed as mean ± SD of replicates of a representative experiment (n = 3). **P = 0.001, by 2-tailed Student’s t test. (D–F) PC3 cells were treated with the indicated increasing concentrations of the oxidative stimuli DMNQ (D), H2O2 (E), and paraquat (PQ, F) and analyzed by Western blotting. Bottom panels (E and F): Densitometric quantification of SDHA, SDHB, or Prx-SO3 protein bands. Data are expressed as mean ± SD (n = 3). *P < 0.05; **P < 0.01; by ANOVA and Bonferroni’s post-test. (G) PC3 shRNA-SNPH #0 cells were treated with the mitochondrial superoxide scavenger MT and incubated with CHX, and cell extracts harvested at the indicated time intervals after release (h) were analyzed by Western blotting. (H) Densitometric quantification of SDHA, SDHB, or COX-IV proteins bands from the experiment in G. Data are expressed as mean ± SD (n = 4). The statistical analyses are as follows: SDHA, 2 hours, NS; 4 hours, P = 0.001; 6 hours, NS; 8 hours, NS; 10 hours, P = 0.033; SDHB, NS for all time points; COX-IV, NS for all time points by 2-tailed Student’s t test.
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