Original contributionHypoxia-inducible adenosine A2B receptor modulates proliferation of colon carcinoma cells
Introduction
Adenosine regulates a wide variety of physiological processes by interacting with adenosine receptors. Adenosine receptors are G protein-coupled purinergic receptors, generally regarded as 4 subtypes referred to as adenosine receptor A1 (ADORA1), A2A (ADORA2A), A2B (ADORA2B), and A3 (ADORA3). Each adenosine receptor is encoded by a separate gene with different functions and tissue distribution [1]. ADORA1 together with ADORA2A play roles in the heart, regulating myocardial oxygen consumption and coronary blood flow. Both ADORA1 and ADORA2A also have important roles in the brain, regulating the release of neurotransmitters such as dopamine and glutamine [2], [3], [4], [5]. Furthermore, ADORA2A has antiinflammatory effects throughout the body [6]. ADORA2B and ADORA3 are mainly peripherally located and are involved in processes such as inflammation and immune response.
Pharmacological tools such as radioligands, selective agonists, and selective antagonists of adenosine receptors have revealed detailed signal transduction of each adenosine receptor subtype. Activation of ADORA1 and ADORA3 decreases cyclic adenosine monophosphate (cAMP) concentration and raises intracellular Ca2+ levels through a pathway involving phospholipase C activation [7], [8]. On the other hand, the ADORA2A and ADORA2B subtypes are associated with stimulatory G-proteins, and activation of these 2 receptor subtypes causes activation of adenylate cyclase and phospholipase C [9]. These findings imply that extracellular adenosine, as a ligand of adenosine receptors, has different biologic effects depending on the expression and the distribution of adenosine receptor subtypes.
More recently, the adenosine-adenosine receptor pathway has been shown to modulate cell proliferation and differentiation, and apoptosis of tumor cells [10], [11], [12]. Reports indicate that adenosine accumulates in solid tumors, and a high concentration of adenosine stimulates tumor growth and tumor angiogenesis [11], [13]. Also, cell surface CD73, which produces extracellular adenosine via ecto-5′-nucleotidase activity, is increased in human cancer cells [14]. Furthermore, some studies showed pro- or antimitogenic effects of ADORA1, ADORA2A, and ADORA3 subtypes [15].
Previous investigations demonstrated an association between ADORA1 and carcinogenesis; expression of this receptor was demonstrated in the human leukemia Jurkat and human melanoma A375 cell lines [16], [17], [18]. Researchers found ADORA2A on cell membranes of different human tumor cell lines including neuroblastoma and malignant melanoma [17], [18], [19]. Adenosine was found to exert its effects on proliferation and cell death mainly through the ADORA3 subtype, which is present in different cell types including astroglial, leukemia, and melanoma cells [17], [18], [20], [21].
There is growing evidence that the adenosine-adenosine receptor pathway may provide promising therapeutic targets in a wide range of conditions such as cerebral and cardiac ischemia, nervous system disorders including dementia and Parkinson disease, and immune and inflammatory disorders [22]. At present, however, few therapeutic targets in the fight against human cancers are available from the “adenosinergic system.”
To investigate the pathophysiological roles of adenosine receptors in human colorectal cancers, we evaluated the expression profiles of all 4 adenosine receptor subtypes in various colorectal tissues by reverse transcriptase polymerase chain reaction (RT-PCR), Western blotting, and immunohistochemistry. Then, we examined the expression profile of adenosine receptors in human colon carcinoma cell lines under normoxic or hypoxic conditions. Moreover, we studied the effect of selective antagonism against adenosine receptors on cell proliferation and on cell invasion of the colorectal cancers.
Section snippets
Case selection
We studied 88 surgical specimens, including tubular adenomas (30 cases) and tubular adenocarcinomas (58 cases), of the colorectum from routine surgical pathology files at University of Yamanashi Hospital, Yamanashi, Japan. Hematoxylin-eosin–stained slides of all cases were reviewed, and the diagnosis was made on the basis of the World Health Organization Classification [23]. Samples of colon mucosa, obtained 8 to 10 cm distant from the colon carcinoma were used as normal colon mucosa (62
Profiles of adenosine receptors in colorectal carcinomas
In this study, we consistently detected ADORA2B messenger RNA (mRNA) by RT-PCR in 5 of 5 colorectal cancer tissues (Fig. 1A). In contrast, only a faint signal was observed in 1 of 5 normal colon tissues. There were no distinct differences in the mRNA expression of ADORA1, ADORA2A, and ADORA3 subtypes between normal colon mucosa and colorectal cancer tissues. Western blotting confirmed that ADORA2B protein was up-regulated in colorectal cancer tissues compared with normal colon tissues (Fig. 1B).
Discussion
In this study, we showed divergent expression of adenosine receptors in human colorectal carcinomas. The expression of ADORA2B was consistently higher than that of ADORA1, ADORA2A, and ADORA3 subtypes in colorectal cancer tissues and in colon cancer cell lines when cultured under a hypoxic state. The ability to retard carcinoma cell growth by pharmacological inhibition of ADORA2B suggests cancer-promoting properties of the ADORA2B subtype.
Recent studies suggest that ADORA2B has important roles
Acknowledgment
We thank Ms Miyuki Ito, Ms Mikiko Yoda, and Mr Yoshihito Koshimizu for technical support, and Ms Kayoko Kono for executive assistance.
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