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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 9

A mitochondrial SNPH “rheostat” for cell proliferation-motility decisions in cancer.

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A mitochondrial SNPH “rheostat” for cell proliferation-motility decision...
An adequate supply of oxygen and nutrients in the tumor microenvironment maintains high levels of SNPH in mitochondria for efficient, “non-leaky” oxidative bioenergetics and low ROS generation. These conditions support continued tumor cell proliferation while halting mitochondrial trafficking to the cortical cytoskeleton as a “regional” energy source to fuel membrane dynamics of cell motility and invasion. Conversely, the emergence of an oxidative and hypoxic microenvironment, typical of advanced tumors, acutely lowers SNPH levels, compromising oxidative phosphorylation complex II integrity and mitochondrial bioenergetics. The resulting increase in ROS inhibits tumor cell proliferation, while promoting increased mitochondrial trafficking to the cortical cytoskeleton and focal adhesion kinase–dependent (FAK-dependent) tumor cell migration and invasion. KIF5, kinesin family member 5; TRAK, trafficking kinesin-binding protein 1.
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