Cancer biology and molecular genetics of A3 adenosine receptor

Abstract

A₃ adenosine receptor (A₃AR) is a cell membrane protein, which has been found to be overexpressed in a large number of cancer types. This receptor plays an important role in cancer by interacting with adenosine. Specifically, A₃AR has a dual nature in different pathophysiological conditions, as it is expressed according to tissue type and stimulated by an adenosine dose-dependent manner. A₃AR activation leads to tumor growth, cell proliferation and survival in some cases, while triggering cytostatic and apoptotic pathways in others. This review aims to describe the most relevant aspects of A₃AR activation and its ligands whereas it summarizes A₃AR activities in cancer. Progress in the field of A₃AR modulators, with a potential therapeutic role in cancer treatment are reported, as well.

Fig. 1. Schematic representation of adenosine receptors.

In normal physiological condition adenosine mediates its activation via four G-protein coupled receptors A1, A₂A, A₂B, and A₃. They are primarily associated with activation and inhibition of Adenylate Cyclase. The accumulation of cAMP is linked to the modulation of ion-channel activity.

Fig. 2. Pro-tumoral and antitumoral activity induced by A₃ adenosine receptor stimulation in different tumors.

The pro-tumoral activity of A₃AR includes the increase of VEGF, HIF-1, MMP-9, angiogenesis, migration, proliferation, and invasion in tumor cells. The A₃AR antitumoral activity leads to the decrease of cell proliferation and migration in several tumor cells and the induction of G-CSF and IL-2 secretion from cells of the immune system.

Fig. 3. A₃ receptor pathways in normoxia/hypoxia conditions.

Cellular pathways activated by the stimulation of the A₃ receptor in normoxia and hypoxia conditions.

Fig. 4. A₃ receptor pathways.

Representation of signal transduction pathways induced by the stimulation of the A3 receptor.

Fig. 5. A₃ receptor ligands.

Chemical structures of (A) N6-(3-Iodobenzyl)adenosine-5′-N-methyluronamide (IB- MECA; CF101); B 2-chloro-N6-(3- iodobenzyl)-adenosine-5′-N-methyluronamide (Cl-IB-MECA; CF102).