Vascular Endothelial Growth Factor Induction by Prostaglandin E2 in Human Airway Smooth Muscle Cells Is Mediated by E Prostanoid EP2/EP4 Receptors and SP-1 Transcription Factor Binding Sites

Bradbury, Dawn A.; Clarke, D. S.; Seedhouse, Claire; Corbett, Lisa; Stocks, Joanne; Knox, Alan J.

doi:10.1074/jbc.m414530200

Cited by 84 publications

(71 citation statements)

References 44 publications

(46 reference statements)

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“…Finally, it has been shown that EP2 and VEGF receptor can cooperate in regulating endothelial cell motility (Bradbury et al, 2005;Chang et al, 2005). In this regard, we show here that stimulation with PGE 2 or angiogenic factors (i.e.…”

Section: Discussionsupporting

confidence: 63%

EP2, a receptor for PGE2, regulates tumor angiogenesis through direct effects on endothelial cell motility and survival

et al. 2006

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Prostaglandin E2 (PGE 2 ), a major cyclooxygenase (COX) metabolite, plays important roles in tumor biology. We studied the role of EP2, a receptor for PGE 2 , in tumor angiogenesis using EP2 knockout mice. We found that deletion of the EP2 receptor impaired tumor angiogenesis and this finding was confirmed by an in vivo corneal angiogenesis model and an ex vivo aortic ring assay. To further characterize the cellular mechanisms of the EP2 receptor in angiogenesis, we isolated primary pulmonary endothelial cells (ECs) from wild-type (wt) and EP2 À/À mice and observed that EP2 À/À ECs exhibited defects in vascular branch formation when compared to wt ECs. In addition, EP2 À/À ECs showed impaired cell motility on collagen-coated surface and they responded poorly to PGE 2 -induced cell migration compared to control cells. However, no difference in cell proliferation was observed between the EP2 À/À and wt Ecs. In addition, EP2 À/À ECs were more susceptible to apoptosis than wt cells under growth factor depletion conditions. Collectively, our data demonstrate that EP2 signaling in endothelium directly regulates tumor angiogenesis by contributing to cell survival and endothelial cell motility. Moreover, our finding suggests that EP2 is a major receptor in PGE 2 -mediated cell motility in ECs.

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Section: Discussionsupporting

confidence: 63%

EP2, a receptor for PGE2, regulates tumor angiogenesis through direct effects on endothelial cell motility and survival

et al. 2006

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“…We show that the CCN1 promoter is activated by either cAMP or following treatment with PGE2, which elevates the internal pool of cAMP in the cells (37). PGE2 is known to promote tumor growth, angiogenesis, and cell migration and to up-regulate VEGF (43). Interestingly, PGE2 was recently found to be activated by CCN1 (30).…”

Section: Creb-mediated Regulation Of Ccn1 At Hypoxia Mol Cancer Res 2mentioning

confidence: 83%

A Key Role for Cyclic AMP-Responsive Element Binding Protein in Hypoxia-Mediated Activation of the Angiogenesis Factor CCN1 (CYR61) in Tumor Cells

Meyuhas¹,

Pikarsky²,

Tavor³

et al. 2008

Molecular Cancer Research

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Hypoxia is a prominent feature of solid tumors known to contribute to malignant progression and therapeutic resistance. Cancer cells adapt to hypoxia using various pathways, allowing tumors to thrive in a low oxygen state. Induction of new blood vessel formation via the secretion of proangiogenic factors is one of the main adaptive responses engaged by tumor cells under hypoxic conditions. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that plays a pivotal role in mediating such responses. In addition, several other transcription factors have also been implicated in hypoxic gene regulation, either independently or in cooperation with HIF-1. In this work, we show that the expression of the angiogenesis-related, immediate early gene CCN1 (formerly known as CYR61), considered to be involved in tumor growth and invasiveness, is enhanced upon hypoxia stress primarily in a protein kinase A and cyclic AMP-responsive element binding protein (CREB) and CRE -dependent manner in various cell lines. The hypoxia-mediated activation of the CCN1 promoter is independent of HIF-1 and HIF-2, as shown by small interfering RNA knockdown. We identify the cis element in the mouse CCN1 promoter responsible for CREB binding to be one of two partial CRE sites present in the promoter. Moreover, we report for the first time that CREB-mediated CCN1 transcription is enhanced in hypoxic regions of tumors in vivo. Identifying and characterizing the molecular mechanisms that govern the response of tumors to hypoxia may be instrumental to identify the tumors that will respond favorably to inhibition of angiogenesis and thus lead to the development of treatments that could complement hypoxia-inducing treatment modalities.

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“…Sp1 is a ubiquitously expressed transcription factor that recognizes GC-rich sequences present in the regulatory sequences of numerous housekeeping genes and those genes that are involved in growth regulation and cancer (34,45). The transcription factor Sp1-response element is present in the promoter region of various genes, including uPA, MMP-9, and VEGF.…”

Section: Discussionmentioning

confidence: 99%

“…Tumor cell-derived VEGF binds to its specific receptors and regulates tumor progression through neovascularization via autocrine and paracrine pathways (43,44). Recent evidence suggested that the VEGF promoter contains an Sp1-response element (45). However, the role of Lck and Syk in H/R-induced VEGF expression in breast cancer is not defined clearly.…”

mentioning

confidence: 99%

Hypoxia Regulates Cross-talk between Syk and Lck Leading to Breast Cancer Progression and Angiogenesis

Chakraborty

Rangaswami

Jain

et al. 2006

Journal of Biological Chemistry

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Vascular Endothelial Growth Factor Induction by Prostaglandin E2 in Human Airway Smooth Muscle Cells Is Mediated by E Prostanoid EP2/EP4 Receptors and SP-1 Transcription Factor Binding Sites

Cited by 84 publications

References 44 publications

EP2, a receptor for PGE2, regulates tumor angiogenesis through direct effects on endothelial cell motility and survival

EP2, a receptor for PGE2, regulates tumor angiogenesis through direct effects on endothelial cell motility and survival

A Key Role for Cyclic AMP-Responsive Element Binding Protein in Hypoxia-Mediated Activation of the Angiogenesis Factor CCN1 (CYR61) in Tumor Cells

Hypoxia Regulates Cross-talk between Syk and Lck Leading to Breast Cancer Progression and Angiogenesis

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