A Mena Invasion Isoform Potentiates EGF-Induced Carcinoma Cell Invasion and Metastasis

Abstract. 5-Fluorouracil (5-FU) has been used as a chemotherapeutic drug for various types of cancer, although the development of resistance remains a major limitation for its use in clinical settings. In the present study, the anti-angiogenic effects of resveratrol and 5-FU either alone or in combination were examined in a B16 murine melanoma model. Co-treatment using resveratrol and 5-FU inhibited cell proliferation more efficiently compared with use of either drug alone and the antiproliferative effect coincided with changes in the expression levels of AMP-activated protein kinase (AMPK), cyclooxygenase-2, vasodilator-stimulated phosphoprotein (VASP) and vascular endothelial growth factor (VEGF). Furthermore, co-treatment with resveratrol and 5-FU reduced tumor growth compared with that in the control group and this growth-inhibitory effect was associated with changes in the expression levels of AMPK, VASP and VEGF. Immunohistochemical staining for angiogenesis demonstrated that co-treatment with resveratrol and 5-FU reduced the number of microvascular vessels compared with that in the control group. These results suggested that co-treatment with resveratrol and 5-FU suppressed cell growth and angiogenesis in B16 murine melanoma tumors.

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“…VASP regulates carcinoma cell invasion and metastasis in vivo and in vitro via epidermal growth factor (EGF) signaling (21).…”

Section: Introductionmentioning

confidence: 99%

Anti-angiogenic effects of resveratrol in combination with 5-fluorouracil on B16 murine melanoma cells

Lee

Koo

Park

et al. 2015

Molecular Medicine Reports

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“…Their overlapping function is modulated by both homo- (Zimmermann et al, 2002) or heterotetramerisation (Gertler et al, 1996) and phosphorylation events (Benz et al, 2009) that control their effect on actin polymerisation. Increased expression of Ena/VASP family members enhances cancer cell invasiveness in vitro and in vivo (Han et al, 2008;Philippar et al, 2008) and correlates with tumour progression in several malignancies (Gurzu et al, 2008;Hu et al, 2008;Toyoda et al, 2009), including lung adenocarcinoma (Dertsiz et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

An siRNA screen identifies RSK1 as a key modulator of lung cancer metastasis

et al. 2011

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We performed a kinome-wide siRNA screen and identified 70 kinases altering cell migration in A549 lung cancer cells. In particular, ribosomal S6 kinase 1 (RSK1) silencing increased, whereas RSK2 and RSK4 downregulation inhibited cell motility. In a secondary collagenbased three-dimensional invasion screen, 38 of our hits cross-validated, including RSK1 and RSK4. In two further lung cancer cell lines, RSK1 but not RSK4 silencing showed identical modulation of cell motility. We therefore selected RSK1 for further investigation. Bioinformatic analysis followed by co-immunoprecipitation-based validation revealed that the actin regulators VASP and Mena interact with RSK1. Moreover, RSK1 phosphorylated VASP on T278, a site regulating its binding to actin. In addition, silencing of RSK1 enhanced the metastatic potential of these cells in vivo using a zebrafish model. Finally, we investigated the relevance of this finding in human lung cancer samples. In isogenically matched tissue, RSK1 was reduced in metastatic versus primary lung cancer lesions. Moreover, patients with RSK1-negative lung tumours showed increased number of metastases. Our results suggest that the findings of our high-throughput in vitro screen can reliably identify relevant clinical targets and as a proof of principle, RSK1 may provide a biomarker for metastasis in lung cancer patients.

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“…With many phenotypic responses occurring on the order of hours to days, most phosphorylation measurements have been on the timescale of minutes to hours, when phosphorylation levels are highest. However, a second class of responses, such as protrusion and calcium signaling, occur within a few seconds after stimulation and suggest an important early regime of signaling activity (7). Although individual, targeted analyses have provided insights into components of signaling activation, systems-level characterization of network activity during this period has been lacking.…”

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confidence: 99%

Early signaling dynamics of the epidermal growth factor receptor

Reddy

Gajadhar

Swenson

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Despite extensive study of the EGF receptor (EGFR) signaling network, the immediate posttranslational changes that occur in response to growth factor stimulation remain poorly characterized; as a result, the biological mechanisms underlying signaling initiation remain obscured. To address this deficiency, we have used a mass spectrometry-based approach to measure system-wide phosphorylation changes throughout the network with 10-s resolution in the 80 s after stimulation in response to a range of eight growth factor concentrations. Significant changes were observed on proteins far downstream in the network as early as 10 s after stimulation, indicating a system capable of transmitting information quickly. Meanwhile, canonical members of the EGFR signaling network fall into clusters with distinct activation patterns. Src homology 2 domain containing transforming protein (Shc) and phosphoinositol 3-kinase (PI3K) phosphorylation levels increase rapidly, but equilibrate within 20 s, whereas proteins such as Grb2-associated binder-1 (Gab1) and SH2-containing tyrosine phosphatase (SHP2) show slower, sustained increases. Proximity ligation assays reveal that Shc and Gab1 phosphorylation patterns are representative of separate timescales for physical association with the receptor. Inhibition of phosphatases with vanadate reveals site-specific regulatory mechanisms and also uncovers primed activating components in the network, including Src family kinases, whose inhibition affects only a subset of proteins within the network. The results presented highlight the complexity of signaling initiation and provide a window into exploring mechanistic hypotheses about receptor tyrosine kinase (RTK) biology.signal transduction | tyrosine phosphorylation | epidermal growth factor receptor | mass spectrometry T he EGF receptor (EGFR) sits atop a complex signaling network that controls cell behavior in response to environmental cues. Cascades of posttranslational modifications initiated from EGFR, notably phosphorylation on tyrosine, serine, and threonine, influence protein-protein interactions and enzymatic activity to activate transcriptional programs that regulate proliferation, differentiation, and apoptosis (1). Mutation or overexpression of EGFR has been identified as an oncogenic driver for many tumor types, making it an attractive target for anticancer therapies (2).Building on decades of specific characterization using traditional biochemistry techniques, platforms such as protein microarrays and mass spectrometry have allowed systems biology to provide a comprehensive picture of intact and aberrant network behavior, which can be used to establish design criteria for therapeutic interventions (3). Manipulating components within the network experimentally and computationally has uncovered many features of the system that influence behaviors such as proliferation and survival (4-6). With many phenotypic responses occurring on the order of hours to days, most phosphorylation measurements have been on the timescale of minutes to...

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A Mena Invasion Isoform Potentiates EGF-Induced Carcinoma Cell Invasion and Metastasis

Cited by 245 publications

References 46 publications

Anti-angiogenic effects of resveratrol in combination with 5-fluorouracil on B16 murine melanoma cells

Anti-angiogenic effects of resveratrol in combination with 5-fluorouracil on B16 murine melanoma cells

An siRNA screen identifies RSK1 as a key modulator of lung cancer metastasis

Early signaling dynamics of the epidermal growth factor receptor

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