Antitumoral Action of Resveratrol Through Adenosinergic Signaling in C6 Glioma Cells

Abstract

Gliomas are the most common and aggressive primary tumors in the central nervous system. The nucleoside adenosine is considered to be one major constituent within the tumor microenvironment. The adenosine level mainly depends on two enzymatic activities: 5′-nucleotidase (5′NT or CD73) that synthesizes adenosine from AMP, and adenosine deaminase (ADA) that converts adenosine into inosine. Adenosine activates specific G-protein coupled receptors named A1, A2A, A2B, and A3 receptors. Resveratrol, a natural polyphenol present in grapes, peanuts, and berries, shows several healthy effects, including protection against cardiovascular, endocrine, and neurodegenerative diseases and cancer. However, the molecular mechanisms of resveratrol actions are not well known. Recently, we demonstrated that resveratrol acts as an agonist for adenosine receptors in rat C6 glioma cells. The present work aimed to investigate the involvement of adenosine metabolism and adenosine receptors in the molecular mechanisms underlying the antitumoral action of resveratrol. Results presented herein show that resveratrol was able to decrease cell numbers and viability and to reduce CD73 and ADA activities, leading to the increase of extracellular adenosine levels. Some resveratrol effects were reduced by the blockade of A1 or A3 receptors by DPCPX or MRS1220, respectively. These results suggest that reduced CD73 activity located in the plasma membrane in addition to a fine-tuned modulatory role of adenosine receptors could be involved, at least in part, in the antiproliferative action of resveratrol in C6 glioma cells.

Resveratrol enhances A1 and hinders A2A adenosine receptors signaling in both HeLa and SH-SY5Y cells: Potential mechanism of its antitumoral action

“…It has been reported that RSV exerts apoptosis by increasing the activity of caspase-9 and caspase-3 while concurrently lowering mitochondrial membrane potential in HeLa cells ( 66 ). This is consistent with our previous report in C6 glioma cells, where acute RSV treatment increased caspase-3 activity without apoptotic bodies in nuclei but also elicited cell growth inhibition and cell cycle arrest in the G 1 phase ( 17 ). Furthermore, RSV strongly diminished proliferation and migration ability in HeLa and SH-SY5Y cell lines as reported here, in agreement with studies performed in murine prostate cancer cells ( 8 ) and HeLa human cervical cancer cells ( 13 ) suggesting that RSV exhibits its antitumoral action in several stages of carcinogenesis.…”

“…We have previously reported how RSV binds to the orthosteric site of adenosine A 2A receptors and acts as a non-selective agonist for adenosine receptors ( 16 ). Moreover, adenosine receptors, mainly A 1 and A 3 , seem to be involved, at least partially, in the antitumoral action of RSV in rat glioma C6 cells ( 17 ). Results presented herein reveal a clear modulation of different adenosine receptors’ gene expression which are not paralleled by changes in the corresponding protein level, mainly in HeLa cells.…”

“…In line with this, activation of A 1 R increased cell viability and reduced apoptotic cells in MCF-7 ( 97 ), while in CW2 colon cancer cells this activation led to cell death ( 98 ), suggesting a tissue-specific role for A 1 R [eviewed in ( 99 )]. Pharmacological blockade of A 1 R and A 3 R with antagonists partially reduced the antitumoral action of RSV In C6 glioma cells ( 17 ). Herein, we have shown that RSV caused overexpression of A 1 R located in the cell surface of both cancer cell lines, which confirms that A 1 R could be related to RSV action.…”

“…Unfortunately, the mode of action of RSV is still poorly understood. Interestingly, one of the signaling pathways that could be related to RSV action is the adenosinergic system ( 16 , 17 ). Adenosine overproduction occurs in all stages of tumorigenesis, from the initial inflammation/local tissue damage to the precancerous niche and the developed tumor ( 18 ).…”

“…Our group has previously demonstrated that RSV binds to the orthosteric binding site of A 2A R and acts as a non-selective agonist for adenosine receptors in rat C6 glioma cells ( 16 ). Moreover, we have reported that adenosine receptors may be involved in the antitumoral action of RSV in C6 glioma cells ( 17 ). However, these findings have not been further corroborated until now in other tumoral cells.…”