Hypoxia-inducible adenosine A2B receptor modulates proliferation of colon carcinoma cells

Ma, Defu; Kondo, Tetsuo; Nakazawa, Tadao; Niu, Dongfeng; Mochizuki, Kazuki; Kawasaki, Tomonori; Yamane, Tetsu; Katoh, Ryohei

doi:10.1016/j.humpath.2010.04.008

Cited by 82 publications

(81 citation statements)

References 30 publications

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“…These results underscore the importance of this receptor subtype as a mediator of antiinflammatory effects triggering the emergency downregulation of overactive immune cells [43]. On the other hand, the relatively high expression levels of adenosine A 2B receptors in cells of the malignant Jurkat T cell line compared to non-malignant PBL cells further indicate an important role of this subtype in malignant cell lines, as previously described [29,32]. The adenosine A 2B receptor may therefore serve as a target to control cell growth and proliferation in these cells.…”

Section: Discussionsupporting

confidence: 81%

“…This indicates that A 2B AR may play a more important role than A 3 AR in this cancer cell line. Both receptor subtypes have previously been postulated to be associated with cancer cell proliferation [27,29,32,42]. Our results indicate that all four AR subtypes are present on human lymphocytic cells, however at different expression levels, resulting in different receptor profiles.…”

Section: Discussionmentioning

confidence: 53%

“…Proliferative or anti-proliferative effects appear to be dependent on the cell type, the distribution of adenosine receptor subtypes, and their expression on the cell surface [22][23][24][25]. A 3 adenosine receptors seem to play an important role [26][27][28], but recent evidence accumulates that A 2B ARs can be upregulated on malignant cells and are involved in the control of tumor growth and development [16,24,[29][30][31][32]. In contrast to these findings, adenosine and various related AR agonists as well as antagonists can trigger apoptosis by receptor-independent mechanisms that require the entry of the compounds into the cells.…”

Section: Introductionmentioning

confidence: 99%

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Antiproliferative effects of selective adenosine receptor agonists and antagonists on human lymphocytes: evidence for receptor-independent mechanisms

Schiedel

Lacher

Linnemann

et al. 2013

Purinergic Signalling

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The effects of standard adenosine receptor (AR) agonists and antagonists on the proliferation of human T lymphocytes, unstimulated and phytohemagglutininstimulated human peripheral blood lymphocytes (PBL), and Jurkat T cells were investigated. Real-time PCR measurements confirmed the presence of all four AR subtypes on the investigated cells, although at different expression levels. A 2A ARs were predominantly expressed in PBL and further upregulated upon stimulation, while malignant Jurkat T cells showed high expression levels of A 1 , A 2A , and A 2B ARs. Cell proliferation was measured by [ 3 H]-thymidine incorporation assays. Several ligands, including the subtype-selective agonists CPA (A 1 ), BAY60-6583 (A 2B ), and IB-MECA (A 3 ), and the antagonists PSB-36 (A 1 ), MSX-2 (A 2A ), and PSB-10 (A 3 ) significantly inhibited cell proliferation at micromolar concentrations, which were about three orders of magnitude higher than their AR affinities. In contrast, further investigated AR ligands, including the agonists NECA (nonselective) and CGS21680 (A 2A ), and the antagonists preladenant (SCH-420814, A 2A ), PSB-1115 (A 2B ), and PSB-603 (A 2B ) showed no or only minor effects on lymphocyte proliferation. The anti-proliferative effects of the AR agonists could not be blocked by the corresponding antagonists. The non-selective AR antagonist caffeine stimulated phytohemagglutinin-activated PBL with an EC 50 value of 104 μM. This is the first study to compare a complete set of commonly used AR ligands for all subtypes on lymphocyte proliferation. Our results strongly suggest that these compounds induce an inhibition of lymphocyte proliferation and cell death through AR-independent mechanisms.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 53%

Section: Introductionmentioning

confidence: 99%

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Antiproliferative effects of selective adenosine receptor agonists and antagonists on human lymphocytes: evidence for receptor-independent mechanisms

Schiedel

Lacher

Linnemann

et al. 2013

Purinergic Signalling

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“…Using a protocol of immunocytofluorescence as previously described, 18 we used primary antibodies and working dilution rates as follows: anti-Runx2 mouse-monoclonal antibody (Abnova; 1:100), anti-SNAI-2/Slug rabbit polyclonal antibody (LS-B554; LifeSpan Biosciences, Seattle, WA, USA; 1:400), anti-MMP-2 rabbit polyclonal antibody (ab37150; Abcam, Cambridge, UK; 1:250) and anti-VEGF-C rabbit polyclonal antibody (no. 18415; Immuno-Biological Laboratories, Gunma, Japan; 1:20).…”

Section: Immunohistocytochemistrymentioning

confidence: 99%

Transcription factor Runx2 is a regulator of epithelial–mesenchymal transition and invasion in thyroid carcinomas

Niu

Kondo

Nakazawa

et al. 2012

Laboratory Investigation

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103

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Runx2/Cbfa1 is a member of the Runt-related transcription factor family and is an essential regulator of osteoblast/ chondrocyte differentiation. Recently, aberrant expression of Runx2 and its oncogenic functions have been identified in the progression and metastasis of human cancers. In this study, we investigated the expression profile of Runx family genes in normal thyroid tissue, non-neoplastic but abnormal thyroid tissue, various types of thyroid tumors and representative human thyroid carcinoma cell lines. Using reverse transcriptase-PCR and western blotting, we found that Runx2 was consistently upregulated in papillary carcinomas (PCs) and thyroid carcinoma cell lines compared with normal thyroid tissue. With immunohistochemistry, we observed negative or focal immunoreactivity of Runx2 in the nuclei of normal thyroid follicular cells. None of the non-neoplastic thyroid tissues, including Graves' thyroid and adenomatous goiter, had diffuse positivity of Runx2. Expression of Runx2 in benign follicular adenomas varied from negative to diffusely positive. Meanwhile, all malignant thyroid tumors showed some Runx2 immunopositivity. It was diffuse and intense in 83% (19/23) of PCs, 71% (5/7) of follicular carcinomas (FCs) and 40% (4/10) of undifferentiated carcinomas (UCs). In thyroid carcinoma cell lines, the MEK inhibitor U0126 suppressed Runx2, suggesting an association of the MAPK/ERK pathway with Runx2 regulation. Effective silencing of Runx2 by short interfering RNA (siRNA) demonstrated downregulation of EMT-related molecules (SNAI2, SNAI3 and TWIST1), MMP2 and vasculogenic factors (VEGFA and VEGFC) in thyroid carcinoma cells. We also confirmed that Runx2 silencing suppresses thyroid carcinoma cell invasion in transwell assays. In conclusion, this study provides insight into the potential molecular mechanism of thyroid cancer invasion. Our data suggest that enhanced Runx2 is functionally linked to tumor invasion and metastasis of thyroid carcinoma by regulating EMT-related molecules, matrix metalloproteinases and angiogenic/lymphangiogenic factors.

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“…It has been reported that the A 2B adenosine receptor (AR) is one of those most abundantly expressed in the human prostate cancer cells [5]. However, the role of the A 2B AR in prostate cancer has not previously been well explored, although it has been studied in several other types of tumors [6][7][8][9]. For example, Ryzhov et al [8], using A 2B AR knockout mice, demonstrated that host A 2B AR promoted the growth of Lewis lung carcinoma.…”

Section: Introductionmentioning

confidence: 99%

A2B adenosine receptor blockade inhibits growth of prostate cancer cells

Wei

Costanzi

Balasubramanian

et al. 2013

Purinergic Signalling

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The role of the A 2B adenosine receptor (AR) in prostate cell death and growth was studied. The A 2B AR gene expression quantified by real-time quantitative RT-PCR and Western blot analysis was the highest among four AR subtypes (A 1 , A 2A , A 2B , and A 3 ) in all three commonly used prostate cancer cell lines, PC-3, DU145, and LNCaP. We explored the function of the A 2B AR using PC-3 cells as a model. The A 2B AR was visualized in PC-3 cells by laser confocal microscopy. The nonselective A 2B AR agonist NECA and the selective A 2B

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Hypoxia-inducible adenosine A2B receptor modulates proliferation of colon carcinoma cells

Cited by 82 publications

References 30 publications

Antiproliferative effects of selective adenosine receptor agonists and antagonists on human lymphocytes: evidence for receptor-independent mechanisms

Antiproliferative effects of selective adenosine receptor agonists and antagonists on human lymphocytes: evidence for receptor-independent mechanisms

Transcription factor Runx2 is a regulator of epithelial–mesenchymal transition and invasion in thyroid carcinomas

A2B adenosine receptor blockade inhibits growth of prostate cancer cells

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