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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 October 2, 2017; First published September 11, 2017
Citation Information: J Clin Invest. 2017;127(10):3755-3769. https://doi.org/10.1172/JCI93172.
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Categories: 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 1

SNPH isoforms.

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SNPH isoforms.
(A) Schematic diagram of the human SNPH locus (based on t...
(A) Schematic diagram of the human SNPH locus (based on the Vertebrate Genome Annotation [Vega] repository; http://vega.archive.ensembl.org/index.html). The position and sequences of intron-exon boundaries, long (L) or short (S) SNPH transcripts, and TaqMan gene expression assays utilized for mRNA amplification of the two SNPH isoforms are indicated. (B) Schematic diagram of L-SNPH or S-SNPH protein isoforms. Pro, proline. (C and D) The indicated normal human tissues (C), normal diploid (MRC5) cells, or tumor cell types (D) were analyzed for L-SNPH or S-SNPH mRNA copy number, and normalized to 1,000 molecules of β-actin. Mean ± SEM (n = 3 per tissue or cell line examined). (E) PC3 cells were fractionated in cytosol (Cyto) or mitochondrial (Mito) extracts and analyzed by Western blotting. TCE, total cell extracts. (F) MCF-7 cells devoid of endogenous SNPH as in D were transfected with SNPH cDNA and analyzed by fluorescence microscopy. Merge image includes the F-actin channel (cyan). Scale bar: 5 μm. (G) PC3 cells were fractionated in sub-mitochondrial extracts containing outer membrane (OM), inter-membrane space (IMS), inner membrane (IM), or matrix (M) and analyzed by Western blotting. The expression of SDHB, cytochrome c (Cyto c), or ClpP was used as a markers for each fraction. MTE, unfractionated mitochondrial extracts.
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