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

The clinical management of neuroendocrine tumours is complex. Such tumours are highly vascular suggesting tumour-related angiogenesis. Adenosine, released during cellular stress, damage and hypoxia, is a major regulator of angiogenesis. Herein, we describe the expression and function of adenosine receptors (A 1 , A 2A , A 2B and A 3 ) in neuroendocrine tumours. Expression of adenosine receptors was investigated in archival human neuroendocrine tumour sections and in two human tumour cell lines, BON-1 (pancreatic) and KRJ-I (intestinal). Their function, with respect to growth and chromogranin A secretion was carried out in vitro. Immunocytochemical data showed that A 2A and A 2B receptors were strongly expressed in 15/15 and 13/18 archival tumour sections. Staining for A 1 (4/18) and A 3 (6/18) receptors was either very weak or absent. In vitro data showed that adenosine stimulated a three-to fourfold increase in cAMP levels in BON-1 and KRJ-1 cells. The non-selective adenosine receptor agonist (adenosine-5′N-ethylcarboxamide, NECA) and the A 2A R agonist (CGS21680) stimulated cell proliferation by up to 20-40% which was attenuated by A 2B (PSB603 and MRS1754) and A 2A (SCH442416) receptor selective antagonists but not by the A 1 receptor antagonist (PSB36). Adenosine and NECA stimulated a twofold increase in chromogranin A secretion in BON-1 cells. Our data suggest that neuroendocrine tumours predominantly express A 2A and A 2B adenosine receptors; their activation leads to increased proliferation and secretion of chromogranin A. Targeting adenosine signal pathways, specifically inhibition of A 2 receptors, may thus be a useful addition to the therapeutic management of neuroendocrine tumours.

Section: Discussionmentioning

confidence: 99%

Adenosine A2A and A2B receptor expression in neuroendocrine tumours: potential targets for therapy

Kalhan

Gharibi

Vazquez

et al. 2011

“…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%

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

Schiedel

Lacher

Linnemann

et al. 2013

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.

“…CXCR4 enhances the proliferative and migratory responses of HT-29 cells [576]. Adenosine can stimulate migration of colon cancer cells and caffeine significantly inhibits this action [473].…”

Section: Injurymentioning

confidence: 99%

Purinergic signalling in the gastrointestinal tract and related organs in health and disease

Burnstock

2013

Purinergic signalling plays major roles in the physiology and pathophysiology of digestive organs. Adenosine 5′-triphosphate (ATP), together with nitric oxide and vasoactive intestinal peptide, is a cotransmitter in nonadrenergic, non-cholinergic inhibitory neuromuscular transmission. P2X and P2Y receptors are widely expressed in myenteric and submucous enteric plexuses and participate in sympathetic transmission and neuromodulation involved in enteric reflex activities, as well as influencing gastric and intestinal epithelial secretion and vascular activities. Involvement of purinergic signalling has been identified in a variety of diseases, including inflammatory bowel disease, ischaemia, diabetes and cancer. Purinergic mechanosensory transduction forms the basis of enteric nociception, where ATP released from mucosal epithelial cells by distension activates nociceptive subepithelial primary afferent sensory fibres expressing P2X3 receptors to send messages to the pain centres in the central nervous system via interneurons in the spinal cord. Purinergic signalling is also involved in salivary gland and bile duct secretion.