The Src Homology 3 Domain-containing Guanine Nucleotide Exchange Factor Is Overexpressed in High-grade Gliomas and Promotes Tumor Necrosis Factor-like Weak Inducer of Apoptosis-Fibroblast Growth Factor-inducible 14-induced Cell Migration and Invasion via Tumor Necrosis Factor Receptor-associated Factor 2

Ensign, Shannon P. Fortin; Mathews, Ian T.; Eschbacher, Jennifer; Loftus, Joseph C.; Symons, Marc; Tran, Nhan L.

doi:10.1074/jbc.m113.468686

Cited by 28 publications

(50 citation statements)

References 54 publications

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“…It has been reported that RhoG and SGEF promote cell migration and invasion in several cell lines including glioblastoma cells, MDA-MB-231 breast cancer cells, PC-3 prostate cancer cells and HeLa cells (Chatterjee et al, 2011;Fortin Ensign et al, 2013;Hiramoto-Yamaki et al, 2010;Katoh et al, 2006;Krishna Subbaiah et al, 2012;Kwiatkowska et al, 2012). Here, we also show that RhoG-and SGEF-deficient SUM159 cells show impaired invasion, despite showing enhanced invadopodia formation and ECM degradation.…”

Section: Discussionsupporting

confidence: 75%

“…These actin-rich dorsal structures share several of its molecular components with invadopodia and podosomes, as well as with focal adhesions, suggesting that some of the signaling pathways controlling their assembly may also be conserved (Buccione et al, 2004). In addition, recent studies have shown that SGEF may play a role during invasion in human papillomavirus-mediated cervical cancer, prostate cancer and glioblastoma (Fortin Ensign et al, 2013;Krishna Subbaiah et al, 2012;Wang et al, 2013). The molecular mechanisms by which SGEF contributes to these processes are unclear.…”

Section: Discussionmentioning

confidence: 99%

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A RhoG-mediated signaling pathway that modulates invadopodia dynamics in breast cancer cells

Goicoechea

Zinn

Awadia

et al. 2017

Journal of Cell Science

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One of the hallmarks of cancer is the ability of tumor cells to invade surrounding tissues and metastasize. During metastasis, cancer cells degrade the extracellular matrix, which acts as a physical barrier, by developing specialized actin-rich membrane protrusion structures called invadopodia. The formation of invadopodia is regulated by Rho GTPases, a family of proteins that regulates the actin cytoskeleton. Here, we describe a novel role for RhoG in the regulation of invadopodia disassembly in human breast cancer cells. Our results show that RhoG and Rac1 have independent and opposite roles in the regulation of invadopodia dynamics. We also show that SGEF (also known as ARHGEF26) is the exchange factor responsible for the activation of RhoG during invadopodia disassembly. When the expression of either RhoG or SGEF is silenced, invadopodia are more stable and have a longer lifetime than in control cells. Our findings also demonstrate that RhoG and SGEF modulate the phosphorylation of paxillin, which plays a key role during invadopodia disassembly. In summary, we have identified a novel signaling pathway involving SGEF, RhoG and paxillin phosphorylation, which functions in the regulation of invadopodia disassembly in breast cancer cells.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

A RhoG-mediated signaling pathway that modulates invadopodia dynamics in breast cancer cells

Goicoechea

Zinn

Awadia

et al. 2017

Journal of Cell Science

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“…Lentiviral vectors containing shRNA targeting SGEF (shSGEF-12 & shSGEF-13) or control empty vector (control) were obtained from Open Biosystems (Fisher Scientific, Pittsburgh, PA) and packaged for lentiviral production as previously described (12). …”

Section: Methodsmentioning

confidence: 99%

“…In GB tumors, SGEF has been shown to be significantly overexpressed, to be correlated with poor patient outcome, and to promote glioma cell migration (12). We report that SGEF expression is increased in a subset of TMZ-resistant derived primary GB xenografts and is up-regulated by TWEAK-Fn14 signaling via NF-κB activity.…”

Section: Introductionmentioning

confidence: 99%

SGEF Is Regulated via TWEAK/Fn14/NF-κB Signaling and Promotes Survival by Modulation of the DNA Repair Response to Temozolomide

Ensign

Roos

Mathews

et al. 2016

Molecular Cancer Research

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Glioblastoma (GB) is the highest grade and most common form of primary adult brain tumors. Despite surgical removal followed by concomitant radiation and chemotherapy with the alkylating agent temozolomide (TMZ), GB tumors develop treatment resistance and ultimately recur. Impaired response to treatment occurs rapidly, conferring a median survival of just fifteen months. Thus, it is necessary to identify the genetic and signaling mechanisms that promote tumor resistance in order to develop targeted therapies to combat this refractory disease. Previous observations indicated that SGEF (ARHGEF26), a RhoG specific guanine nucleotide exchange factor (GEF), is overexpressed in GB tumors and plays a role in promoting TWEAK-Fn14 mediated glioma invasion. Here, further investigation revealed an important role for SGEF in glioma cell survival. SGEF expression is up-regulated by TWEAK-Fn14 signaling via NF-κB activity while shRNA-mediated reduction of SGEF expression sensitizes glioma cells to TMZ-induced apoptosis and suppresses colony formation following TMZ treatment. Nuclear SGEF is activated following TMZ exposure and complexes with the DNA damage repair (DDR) protein BRCA1. Moreover, BRCA1 phosphorylation in response to TMZ treatment is hindered by SGEF knockdown. The role of SGEF in promoting chemotherapeutic resistance highlights a heretofore unappreciated driver, and suggests its candidacy for development of novel targeted therapeutics for TMZ refractory, invasive GB cells. Implication SGEF, as a dual process modulator of cell survival and invasion, represents a novel target for treatment refractory glioblastoma.

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“…Lamellipodia formation in glioma cells under PPF treatment was interrogated as described previously [25]. Briefly, glioma cells were plated onto 10-well glass slides pre-coated with 10 μg/ml laminin at the density of 3000 cells/well for 24 hours at 37°C.…”

Section: Methodsmentioning

confidence: 99%

Propentofylline inhibits glioblastoma cell invasion and survival by targeting the TROY signaling pathway

et al. 2015

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Glioblastoma (GBM) is the most common primary tumor of the CNS and carries a dismal prognosis. The aggressive invasion of GBM cells into the surrounding normal brain makes complete resection impossible, significantly increases resistance to the standard therapy regimen, and virtually assures tumor recurrence. Median survival for newly diagnosed GBM is 14.6 months and declines to 8 months for patients with recurrent GBM. New therapeutic strategies that target the molecular drivers of invasion are required for improved clinical outcome. We have demonstrated that TROY (TNFRSF19), a member of the TNFR super-family, plays an important role in GBM invasion and resistance. Knockdown of TROY expression inhibits GBM cell invasion, increases sensitivity to temozolomide, and prolongs survival in an intracranial xenograft model. Propentofylline (PPF), an atypical synthetic methylxanthine compound, has been extensively studied in Phase II and Phase III clinical trials for Alzheimer’s disease and vascular dementia where it has demonstrated blood-brain permeability and minimal adverse side effects. Here we showed that PPF decreased GBM cell expression of TROY, inhibited glioma cell invasion, and sensitized GBM cells to TMZ. Mechanistically, PPF decreased glioma cell invasion by modulating TROY expression and downstream signaling, including AKT, NF-κB, and Rac1 activation. Thus, PPF may provide a pharmacologic approach to targeting TROY to inhibit cell invasion and reduced therapeutic resistance in GBM.

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Cited by 28 publications

References 54 publications

A RhoG-mediated signaling pathway that modulates invadopodia dynamics in breast cancer cells

A RhoG-mediated signaling pathway that modulates invadopodia dynamics in breast cancer cells

SGEF Is Regulated via TWEAK/Fn14/NF-κB Signaling and Promotes Survival by Modulation of the DNA Repair Response to Temozolomide

Propentofylline inhibits glioblastoma cell invasion and survival by targeting the TROY signaling pathway

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