Expression and function of A<sub>2B</sub> adenosine receptors in the U87MG tumor cells

Zeng, Dewan; Maa, Tenning; Wang, Uerica; Feoktistov, Igor; Biaggioni, Italo; Belardinelli, Luiz

doi:10.1002/ddr.10212

Cited by 30 publications

(26 citation statements)

References 19 publications

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“…Furthermore, our results indicate that, in tumor colon hypoxic cells, adenosine increases VEGF promoter activity via the HIF-1 pathway and that caffeine is able to block this effect. It has been reported, in previous studies, that A 2B receptors stimulate IL-8 production in normoxic conditions (Zeng et al, 2003). In this study, we found that also in hypoxia, there is a modulation in IL-8 levels mediated by the adenosine receptor agonist NECA.…”

Section: Discussionsupporting

confidence: 75%

Caffeine Inhibits Adenosine-Induced Accumulation of Hypoxia-Inducible Factor-1α, Vascular Endothelial Growth Factor, and Interleukin-8 Expression in Hypoxic Human Colon Cancer Cells

Merighi

Benini²,

Mirandola³

et al. 2007

Mol Pharmacol

146

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Frequent coffee consumption has been associated with a reduced risk of colorectal cancer in a number of case-control studies. Coffee is a leading source of methylxanthines, such as caffeine. The induction of vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) is an essential feature of tumor angiogenesis, and the hypoxia-inducible factor-1 (HIF-1) transcription factor is known to be a key regulator of this process. In this study, we investigated the effects of caffeine on HIF-1 protein accumulation and on VEGF and IL-8 expression in the human colon cancer cell line HT29 under hypoxic conditions. Our results show that caffeine significantly inhibits adenosineinduced HIF-1␣ protein accumulation in cancer cells. We show that HIF-1␣ and VEGF are increased through A 3 adenosine receptor stimulation, whereas the effects on IL-8 are mediated via the A 2B subtype. Pretreatment of cells with caffeine significantly reduces adenosine-induced VEGF promoter activity and VEGF and IL-8 expression. The mechanism of caffeine seems to involve the inhibition of the extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and Akt, leading to a marked decrease in adenosine-induced HIF-1␣ accumulation, VEGF transcriptional activation, and VEGF and IL-8 protein accumulation. From a functional perspective, we observe that caffeine also significantly inhibits the A 3 receptor-stimulated cell migration of colon cancer cells. Conditioned media prepared from colon cells treated with an adenosine analog increased human umbilical vein endothelial cell migration. These data provide evidence that adenosine could modulate the migration of colon cancer cells by an HIF-1␣/VEGF/IL-8-dependent mechanism and that caffeine has the potential to inhibit colon cancer cell growth.Coffee and tea are the most commonly consumed beverages in the world (Fredholm, 1999). Results of epidemiological studies have not resolved whether coffee consumption is related to colorectal cancer risk. A report by the World Cancer Research Fund concluded that the available evidence was not sufficient to draw any firm conclusions about a decreased risk of colorectal cancer associated with coffee consumption (World Cancer Research Fund/American Institute for Cancer Research, 1997). However, some researchers contend that a link between high consumption of coffee and a low incidence Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org. doi:10.1124/mol.106.032920.ABBREVIATIONS: IL-8, interleukin-8; Cl-IB-MECA, N 6 (3-iodobenzyl)2-chloroadenosine-5ЈN-methyluronamide; DPCPX, 1,3-dipropyl-8-cyclopentylxanthine; MRE 2029F20, N-benzo[1,3]dioxol-5-yl-2-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yloxy

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Section: Discussionsupporting

confidence: 75%

Caffeine Inhibits Adenosine-Induced Accumulation of Hypoxia-Inducible Factor-1α, Vascular Endothelial Growth Factor, and Interleukin-8 Expression in Hypoxic Human Colon Cancer Cells

Merighi

Benini²,

Mirandola³

et al. 2007

Mol Pharmacol

146

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“…This view has been supported by a large body of evidence provided by pharmacological analysis of adenosinedependent cytokine and growth factor secretion in various cells, tissues, and organs (8,11,13,18,(31)(32)(33)(34)(35)(36)(37)(38). Pharmacological inhibition of A 2B receptors significantly reduced elevations in proinflammatory cytokines as well as mediators of airway remodeling induced by high adenosine levels in the lungs of ADA-deficient mice (8).…”

Section: Discussionmentioning

confidence: 95%

Effect of A2B Adenosine Receptor Gene Ablation on Proinflammatory Adenosine Signaling in Mast Cells

Ryzhov¹,

Zaynagetdinov²,

Goldstein

et al. 2008

The Journal of Immunology

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We have previously shown that A2B adenosine receptors (AR) play a pro‐inflammatory/pro‐angiogenic role, upregulating production of Th2 cytokines and angiogenic factors in human HMC‐1 mast cells.1,2 However, the pro‐inflammatory role of A2bAR in mast cells was recently questioned by a study that found an enhanced antigen‐induced degranulation of A2bAR knockout (A2BKO) mouse bone marrow‐derived mast cells (BMMCs).3 The authors interpreted this as evidence of anti‐inflammatory actions of A2BAR in BMMCs and suggested that A2BAR antagonists with inverse agonist activity could promote activation of mast cells. Here, we revisited these conclusions by studying the effect of genetic A2BAR ablation on adenosine‐dependent regulation of BMMCs. Our results show that genetic ablation of A2BAR had no effect on adenosine‐dependent potentiation of antigen‐induced degranulation, but abrogated adenosine‐dependent stimulation of IL‐13 and VEGF secretion. A2BAR antagonists with inverse agonist activity inhibited A2BAR‐dependent secretion, but did not mimic the enhanced antigen‐induced degranulation observed in A2BKO BMMCs. Thus, our study confirmed the pro‐inflammatory role of mast cell A2BAR and demonstrated anti‐inflammatory actions of A2BAR antagonists. Supported by NIH.

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“…In support of this, A 2B AR knockout mice, administered Lewis lung carcinoma, demonstrated reduced tumor growth and survival times (Ryzhov et al, 2008). Studies performed on U87 MG human glioblastoma cells only detected transcripts for A 1 , A 2A and A 2B ARs, but no transcript for A 3 AR (Zeng et al, 2003). However, Merighi et al (2006) were able to detect A 3 AR in these cells.…”

Section: Adenosine Receptors In Cancermentioning

confidence: 80%

Targeting Adenosine Receptors for the Treatment of Melanoma

Jajoo¹,

Sheth²,

Mukherjea³

et al. 2011

Breakthroughs in Melanoma Research

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Expression and function of A_2B adenosine receptors in the U87MG tumor cells

Cited by 30 publications

References 19 publications

Caffeine Inhibits Adenosine-Induced Accumulation of Hypoxia-Inducible Factor-1α, Vascular Endothelial Growth Factor, and Interleukin-8 Expression in Hypoxic Human Colon Cancer Cells

Caffeine Inhibits Adenosine-Induced Accumulation of Hypoxia-Inducible Factor-1α, Vascular Endothelial Growth Factor, and Interleukin-8 Expression in Hypoxic Human Colon Cancer Cells

Effect of A2B Adenosine Receptor Gene Ablation on Proinflammatory Adenosine Signaling in Mast Cells

Targeting Adenosine Receptors for the Treatment of Melanoma

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Expression and function of A2B adenosine receptors in the U87MG tumor cells

Cited by 30 publications

References 19 publications

Caffeine Inhibits Adenosine-Induced Accumulation of Hypoxia-Inducible Factor-1α, Vascular Endothelial Growth Factor, and Interleukin-8 Expression in Hypoxic Human Colon Cancer Cells

Caffeine Inhibits Adenosine-Induced Accumulation of Hypoxia-Inducible Factor-1α, Vascular Endothelial Growth Factor, and Interleukin-8 Expression in Hypoxic Human Colon Cancer Cells

Effect of A2B Adenosine Receptor Gene Ablation on Proinflammatory Adenosine Signaling in Mast Cells

Targeting Adenosine Receptors for the Treatment of Melanoma

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Product

Resources

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Expression and function of A_2B adenosine receptors in the U87MG tumor cells