Endothelial Monocyte Activating Polypeptide II Induces Endothelial Cell Apoptosis and May Inhibit Tumor Angiogenesis

Berger, Adam C.; Alexander, H. Richard; Tang, Guangquing; Wu, Peter; Hewitt, Stephen M.; Turner, Ewa M.; Krüger, Erwin A.; Figg, William D.; Grove, Andrew D.; Kohn, Elise C.; Stern, David M.; Libutti, Steven K.

doi:10.1006/mvre.2000.2249

Cited by 90 publications

(63 citation statements)

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“…7 Although EMAP II sensitizes tumors to the antitumor effects of tumor necrosis factor-a 8,9 by inducing the expression of tumor necrosis factor-a receptor-1, 10 it has in its own right been shown to induce apoptosis of ECs and inhibits proliferation, vascularization and neovessel formation. 11,12 In addition, EMAP II has been shown to suppress primary and metastatic tumor growth by antiangiogenic properties 11 and to reduce vascular endothelial growth factor (VEGF) expression, 13 which itself facilitates tumor growth through induction of angiogenesis.…”

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confidence: 99%

Endothelial monocyte activating polypeptide II interferes with VEGF-induced proangiogenic signaling

Awasthi

Schwarz

Verma

et al. 2009

Laboratory Investigation

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Endothelial monocyte activating polypeptide II (EMAP II) is a proinflammatory cytokine with antiangiogenic properties. EMAP II functions as a potent inhibitor of primary and metastatic tumor growth, has strong inhibitory effects on endothelial cells (ECs), and can reduce intratumoral expression of the angiogenesis inducer vascular endothelial growth factor (VEGF). VEGF influences EC functions such as proliferation, migration, survival and tube formation. Therapeutic strategies that target VEGF have been demonstrated to reduce the tumor growth. We investigated the effects of EMAP II on VEGF-induced angiogenesis signaling. Primary human fetal lung ECs (HFLECs) and human umbilical vein ECs (HUVECs) were grown in E-Stim medium. Protein binding was analyzed using enzyme-linked immunosorbent assay (ELISA). Protein expression was determined by western blot analysis. EC proliferation and migration was determined using WST-1 reagent and transwell membrane, respectively. EMAP II efficiently and dose dependently binds to VEGF receptor 1 (VEGFR1) and VEGF receptor 2 (VEGFR2) as observed by ELISA. B max values for VEGFR1 and VEGFR2 were 0.45 and 0.17, respectively. In addition, EMAP II inhibited binding of VEGF to VEGFR1 and VEGFR2. EMAP II significantly reduced VEGF-induced expression of phosphorylated VEGFR1 (in HFLEC and HUVEC) by 450%, and of phosphorylated VEGFR2 (in HUVEC) by 66%. EMAP II also inhibited downstream VEGF signaling. Although VEGF-induced phosphorylation of Akt, Erk1/2, p38 and Raf 2.8-, 1.5-, 2.2-and 3.6-fold, respectively, EMAP II preincubation blocked this induction in phosphorylation to control levels. VEGF-induced EC proliferation 2.5-fold, and EMAP II pretreatment abrogated this effect. Similarly, VEGF-induced EC migration (2.5-fold) was significantly inhibited by EMAP II. These finding suggest that inhibition of VEGF signaling is one possible antiangiogenic mechanism of EMAP II, which may explain its in vivo antitumor activity and delineate therapeutic strategies to enhance anti-VEGF therapy to inhibit tumor growth.

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confidence: 99%

Endothelial monocyte activating polypeptide II interferes with VEGF-induced proangiogenic signaling

Awasthi

Schwarz

Verma

et al. 2009

Laboratory Investigation

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“…angiogenic cord formation by ECs [8,18,32]. Here we show that EMAP-II inhibits angiogenic cord formation by regulation of HIF-1α.…”

Section: Discussionmentioning

confidence: 57%

“…It has been shown that under hypoxic conditions, ECs cultured in the absence of growth factors survive and form tube like structures via HIF-1α expression [8,18,32]. We also know that EMAP-II inhibits angiogenesis via inhibition of Fig.…”

Section: Discussionmentioning

confidence: 98%

“…Under similar conditions, various cell types (monocytes, macrophages and tumor cells) secret EMAP-II, a multifunctional cytokine cleaved from its precursor Pro-EMAP. EMAP-II has been shown to have anti-angiogenic properties including the inhibition of EC proliferation, tube formation, adhesion to fibronectin and induction of EC apoptosis [8,19] (Fig. 9).…”

Section: Discussionmentioning

confidence: 99%

“…It induces tissue factor (TF) expression to modulate coagulant responses, induces the expression of P-and E-selectin and upregulates tumor necrosis factor-α (TNF-α) receptors [7][8][9]. It inhibits EC proliferation, migration, angiogenic cord formation and induces apoptosis [10].…”

Section: Introductionmentioning

confidence: 99%

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Endothelial monocyte activating polypeptide-II modulates endothelial cell responses by degrading hypoxia-inducible factor-1alpha through interaction with PSMA7, a component of the proteasome

Tandle

Calvani²,

Uranchimeg³

et al. 2009

Experimental Cell Research

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The majority of human tumors are angiogenesis dependent. Understanding the specific mechanisms that contribute to angiogenesis may offer the best approach to develop therapies to inhibit angiogenesis in cancer. Endothelial monocyte activating polypeptide-II (EMAP-II) is an anti-angiogenic cytokine with potent effects on endothelial cells (ECs). It inhibits EC proliferation and cord formation, and it suppresses primary and metastatic tumor growth in-vivo. However, very little is known about the molecular mechanisms behind the anti-angiogenic activity of EMAP-II. In the present study, we explored the molecular mechanism behind the anti-angiogenic activity exerted by this protein on ECs. Our results demonstrate that EMAP-II binds to the cell surface α5β1 integrin receptor. The cell surface binding of EMAP-II results in its internalization into the cytoplasmic compartment where it interacts with its cytoplasmic partner PSMA7, a component of the proteasome degradation pathway. This interaction increases hypoxia-inducible factor 1-alpha (HIF-1α) degradation under hypoxic conditions. The degradation results in the inhibition of HIF-1α mediated transcriptional activity as well as HIF-1α mediated angiogenic sprouting of ECs. HIF-1α plays a critical role in angiogenesis by activating a variety of angiogenic growth factors. Our results suggest that one of the major anti-angiogenic functions of EMAP-II is exerted through its inhibition of the HIF-1α activities.Published by Elsevier Inc.

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Progress in antiangiogenic gene therapy of cancer

Feldman

Libutti

2000

Cancer

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Endothelial Monocyte Activating Polypeptide II Induces Endothelial Cell Apoptosis and May Inhibit Tumor Angiogenesis

Cited by 90 publications

References 20 publications

Endothelial monocyte activating polypeptide II interferes with VEGF-induced proangiogenic signaling

Endothelial monocyte activating polypeptide II interferes with VEGF-induced proangiogenic signaling

Endothelial monocyte activating polypeptide-II modulates endothelial cell responses by degrading hypoxia-inducible factor-1alpha through interaction with PSMA7, a component of the proteasome

Progress in antiangiogenic gene therapy of cancer

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