TY - JOUR
T1 - Syntaphilin controls a mitochondrial rheostat for proliferation-motility decisions in cancer
AU - Caino, M. Cecilia
AU - Seo, Jae Ho
AU - Wang, Yuan
AU - Rivadeneira, Dayana B.
AU - Gabrilovich, Dmitry I.
AU - Kim, Eui Tae
AU - Weeraratna, Ashani T.
AU - Languino, Lucia R.
AU - Altieri, Dario C.
N1 - Funding Information:
The authors thank Frederick Keeney (Wistar Institute) for assistance with time-lapse microscopy. This work was supported by NIH grants P01 CA140043 (DCA, DIG, and LRL), R01 CA78810 and CA190027 (DCA), R01 CA089720 (LRL), and F32 CA177018 (MCC); the Office of the Assistant Secretary of Defense for Health Affairs through the Prostate Cancer Research Program under award W81XWH-13-1-0193 (DCA); and a Challenge Award from the Prostate Cancer Foundation (PCF) to MCC, DIG, LRL, and DCA. Support for Core Facilities utilized in this study was provided by Cancer Center Support Grant (CCSG) CA010815 to the Wistar Institute.
PY - 2017/10/2
Y1 - 2017/10/2
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI93172
DO - 10.1172/JCI93172
M3 - Article
C2 - 28891816
AN - SCOPUS:85030559893
VL - 127
SP - 3755
EP - 3769
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 10
ER -