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J Clin Invest. 2017 Oct 2;127(10):3755-3769. doi: 10.1172/JCI93172. Epub 2017 Sep 11.

Syntaphilin controls a mitochondrial rheostat for proliferation-motility decisions in cancer.

Author information

1
Prostate Cancer Discovery and Development Program.
2
Tumor Microenvironment and Metastasis Program, and.
3
Translational Tumor Immunology Program, The Wistar Institute, Philadelphia, Pennsylvania, USA.
4
Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
5
Department of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.

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.

PMID:
28891816
PMCID:
PMC5617650
DOI:
10.1172/JCI93172
[Indexed for MEDLINE]
Free PMC Article

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