Vascular Endothelial Growth Factor Up-regulation via p21-activated Kinase-1 Signaling Regulates Heregulin-β1-mediated Angiogenesis

Bagheri‐Yarmand, Rozita; Vadlamudi, Ratna K.; Wang, Rui An; Mendelsohn, John; Kumar, Rakesh

doi:10.1074/jbc.m006150200

Cited by 119 publications

(81 citation statements)

References 26 publications

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“…In this regard, previous studies have shown that Gq-coupled receptors such as those for bombesin/ GRP can phosphorylate receptors of the ErbB/HER family by transactivation (Prenzel et al, 1999). It has also been revealed that EGFR and HER-2 can potentiate tumour cell adhesion to endothelial cells, by enhancing the synthesis of hypoxia-inducible factor (HIF)-1a, and/or carbonic anhydrase-9 (Giatromanolaki et al, 2001;Laughner et al, 2001) through a PI3 kinase-dependent pathway (Bagheri-Yarmand et al, 2000). Several dozens of HIF-1 targets are known, including the genes encoding VEGF and IGF-II.…”

Section: Discussionmentioning

confidence: 99%

Bombesin antagonists inhibit proangiogenic factors in human experimental breast cancers

et al. 2004

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The overexpression of angiogenic factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and insulin-like growth factors (IGFs) plays a role in the migration and proliferation of endothelial cells in many cancers. Consequently, we investigated the effects of bombesin/gastrin-releasing peptide (GRP) antagonists on the expression of these angiogenic factors, the activities of matrix metalloproteinases (MMPs)-2 and -9, as well as the vascular density in MDA-MB-435 human oestrogenindependent breast cancers. Nude mice bearing orthotopic xenografts of MDA-MB-435 breast cancers were treated with bombesin/ GRP antagonists for 6 weeks. Daily administration of 20 mg of RC-3095 or 10 mg of RC-3940-II significantly decreased the weight of MDA-MB-435 cancers by 44 and 53%, respectively. The inhibition of tumour growth was associated with a substantial reduction in the expression of mRNA and protein levels of basic fibroblast growth factor (bFGF), IGF-II and VEGF-A in the tumours. Both bombesin/GRP antagonists significantly decreased the vessel density of the tumours by about 37%, as shown by immunohistochemical detection of vessels on tumour slides. Gelatinolytic activities, detected by zymography, revealed a 33 -46% reduction in MMP-9 activity after the treatment with either antagonist. In vitro studies revealed that MDA-MB-435 cells secrete bFGF, IGF-II and VEGF-A, and the secretion of these factors is inhibited by RC-3095 and RC-3940-II. This study demonstrates the antiangiogenic effect of bombesin/GRP antagonists RC-3095 and RC-3940-II, and underscores their possible therapeutic application for treatment of breast cancers.

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Section: Discussionmentioning

confidence: 99%

Bombesin antagonists inhibit proangiogenic factors in human experimental breast cancers

et al. 2004

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“…However, the signaling pathways that regulate VEGF expression remain controversial. The p21-activated kinase-1 (PAK-1), phosphatidylinositol 3 0 -kinase (PI3K), and mitogen-activated protein (MAP) kinases signaling pathways have all been implicated in the regulation of VEGF expression in breast cancer cells in different studies (Bagheri-Yarmand et al, 2000;Xiong et al, 2001;Chelouche-Lev et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy

et al. 2006

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We determined the impact of HER2 signaling on two proangiogenic factors, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8), and on an antiangiogenic factor, thrombospondin-1 (TSP-1). Re-expression of HER2 in MCF-7 and T-47D breast cancer cells that endogenously express low levels of HER2 resulted in elevated expression of VEGF and IL-8 and decreased expression of TSP-1. Inhibition of HER2 with a humanized anti-HER2 antibody (trastuzumab, or Herceptin s ) or a retrovirus-mediated small interfering RNA against HER2 (siHER2) decreased VEGF and IL-8 expression, but increased TSP-1 expression in BT474 breast cancer cells that express high levels of HER2. These in vitro results were further evaluated by treatment of BT474 xenografts in immunosuppressed mice with trastuzumab. Trastuzumab inhibited growth of BT474 xenografts and decreased microvascular density associated with downregulation of VEGF and IL-8 and with upregulation of TSP-1 expression. Inhibiting the PI3K-AKT pathway decreased VEGF and IL-8 expression. AKT1 overexpession increased VEGF and IL-8 expression, but did not increase TSP-1 expression. A p38 kinase inhibitor, SB203580, instead blocked TSP-1 expression and a p38 activator, MKK6, increased TSP-1 expression. Trastuzumab stimulated sustained p38 activation and SB203580 attenuated the TSP-1 upregulation induced by trastuzumab. HER2 signaling therefore influences the equilibrium between pro-and antiangiogenic factors via distinct signaling pathways. Trastuzumab inhibits angiogenesis and tumor growth, at least in part, through activation of the HER2-p38-TSP-1 pathway and inhibition of the HER2-PI3K-AKT-VEGF/IL-8 pathway.

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“…HER2 overexpression or heregulin stimulation have been shown to induce VEGF mRNA and protein expression [121,122]. The use of a specific neutralizing monoclonal antibody against HER2 (4D5) in the treatment of breast cancer cells results in a dose-dependent inhibition of VEGF expression [123].…”

Section: Erbb Family Receptorsmentioning

confidence: 99%

Interplay between receptor tyrosine kinases and hypoxia signaling in cancer

Glück

Aebersold

Zimmer

et al. 2015

The International Journal of Biochemistry & Cell Biology

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Vascular Endothelial Growth Factor Up-regulation via p21-activated Kinase-1 Signaling Regulates Heregulin-β1-mediated Angiogenesis

Cited by 119 publications

References 26 publications

Bombesin antagonists inhibit proangiogenic factors in human experimental breast cancers

Bombesin antagonists inhibit proangiogenic factors in human experimental breast cancers

HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy

Interplay between receptor tyrosine kinases and hypoxia signaling in cancer

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