Adenosine exerts potent anticancer effects through diverse signaling pathways

Abstract

Abstract Purpose Evidence has shown that extracellular adenosine induces apoptosis in variety of cancer cells, mainly through two pathways: an intrinsic pathway relative to adenosine uptake into the cells, and an extrinsic pathway involving the adenosine receptors. We elucidated the mechanisms underlying the adenosine-induced anticancer effects. Study section and results Extrinsic pathway analysis showed that extracellular adenosine induces apoptosis in CW2 human colon cancer and RCR-1 rat astrocytoma cells through the A 1 adenosine receptor; in Caco-2 human colon cancer and HepG2 human hepatoma cells through the A 2a adenosine receptor; and through the A 3 adenosine receptor in A549, Lu-65, and SBC-3 human lung cancer cells, RCC4-VHL human renal cancer cells, 5637 human bladder cancer cells, and human malignant pleural mesothelioma cells. In the intrinsic pathways, intracellularly transported adenosine induces apoptosis in GT3-TKB human lung cancer cells, human malignant pleural mesothelioma cells, HuH-7 and HepG2 human hepatoma cells, and MCF-7 human breast cancer cells by a) activating AMPK, b) upregulating p53, c) downregulating c-FLIP expression, d) neutralizing caspase-3 inhibition due to inhibition of apoptosis protein (IAP) in cooperation with DIABLO, e) accumulating AMID in the nucleus, f) regulating apoptosis-related gene transcription, or g) promoting GATA-2-regulated p53 gene transcription. Conclusions Adenosine exerts its anticancer action on a wide variety of cancer cell types through diverse signaling pathways. Therefore, adenosine and its signaling cascades can be useful as possible targets in the development of promising anticancer therapies.