Adenosine: Essential for life but licensed to kill

Abstract

In this issue of Molecular Cell, Long et al. (Long et al., 2013) report a cell death priming mechanism activated by p53 that senses extracellular adenosine accumulated following chemotherapy or hypoxia, providing a novel connection between adenosine signaling and apoptosis.

For many years the notion that cells could release an essential molecule such as adenosine triphosphate (ATP) was received with considerable skepticism. It is now evident, however, that the release of purines and pyrimidines is a fundamental intercellular communication mechanism in a variety of cell types and organisms (Stagg and Smyth, 2010). Four decades after Burnstock et al. described the release of extracellular ATP by non-adrenergic inhibitory nerves (Burnstock et al., 1970), purinergic signaling is now a widely accepted concept and an increasing area of investigation. For example, extracellular ATP and adenosine, the metabolite generated from the breakdown of ATP by ecto-nucleotidases, have been implicated as signaling molecules in a broad range of cellular pathways including pain, taste, phagocytosis and angiogenesis (Elliott et al., 2009; Gessi et al., 2011; Sawynok and Liu, 2003). The extracellular concentration of adenosine is constant under basal conditions in most tissues, but it can rapidly increase almost 100-fold in hypoxic tissue and in response to inflammation (Fredholm, 2007; Stagg and Smyth, 2010). Not surprisingly, adenosine accumulates in the extracellular tissue surrounding tumors because the tumor microenvironment is hypoxic and can trigger a strong inflammatory response (Di Virgilio, 2012). The mechanism by which normal and cancer cells sense and respond to increased levels of adenosine is not completely understood, and the implications of an adenosine-sensing mechanism in cancer have been unclear. In this issue of Molecular Cell, Long et al. (Long et al., 2013) shed light onto this unknown mechanism. The authors identify the adenosine receptor, ADORA2B (A2B), as a direct p53 target gene. Importantly, they demonstrate that an apoptotic program is triggered under conditions in which extracellular adenosine accumulates and p53 induces A2B expression. Long et al. investigated the forms of cellular stress that could induce this p53-mediated A2B expression and found that certain genotoxic (e.g. cisplatin) as well as non-genotoxic stimuli (e.g. methotrexate), induce A2B expression. These studies also revealed that treatment with cisplatin not only induced p53-dependent expression of endogenous A2B, but also caused a considerable increase in extracellular adenosine. Strikingly, in this context, the authors found that A2B signaling contributes to about 50% of the cell death. These results indicate that upregulation of the A2B receptor represents a p53-induced priming mechanism that stimulates apoptosis in response to accumulation of extracellular adenosine. While previous reports have demonstrated the production of extracellular adenosine in response to various cellular stresses, this is the first indication that adenosine also accumulates in response to a chemotherapeutic drug and that extracellular adenosine accumulation is responsible for a significant proportion of the cell death observed.

It is well known that tumorigenesis is linked to the acquisition of mutations in p53 that render malignant cells resistant to apoptotic signals. Apoptosis is regulated through the action of the Bcl-2 family of proteins (Chipuk et al., 2010). Anti-apoptotic proteins such as Bcl-2, Bcl-XL and Mcl-1 have the ability to protect the mitochondria from permeabilization induced by the pro-apoptotic members Bax and Bak. Apoptosis is initiated when the BH3-only proteins trigger the direct activation of Bax and Bak (e.g. Bid, Bim, Puma) and/or neutralize the anti-apoptotic Bcl-2, Bcl-XL, and Mcl-1 (e.g. Bad, Noxa, Hrk, Bik) (Martinou and Youle, 2011). Long and collaborators examined the specific mechanism involved in the A2B-mediated cell death and found that A2B-mediated signaling decreased the levels of both Bcl-2 and Bcl-XL. Interestingly, they also found Puma to be induced and required for adenosine-induced death. These findings represent a critical link between adenosine signaling and the p53 tumor suppressor pathway. In addition, these results imply that cells possess a unique signaling pathway capable of sensing tumor-associated metabolic changes in the microenvironment and eliminating the transformed cells.

The findings by Long et al. adds to the astonishingly numerous mechanisms by which p53 regulates cell survival and death, yet also raises a number of intriguing questions. What is the specific mechanism by which A2B signaling promotes Bcl-2 and Bcl-XL downregulation and Puma induction? Does A2B-signaling also contribute to other tumor suppressive functions of p53 such as growth arrest and DNA repair? In addition, the mechanisms by which adenosine accumulates in the extracellular environment remain unexplored. It would also be interesting to determine whether inactivation of adenosine secretion or signaling is associated with the development of chemoresistance. Importantly, experiments probing the role of the adenosine signaling pathway in in vivo models will shed light on its role in tumorigenesis and association with chemoresistance. This research by Long et al. indeed provides a new perspective for the development of innovative therapeutics against cancer. It also refocuses our attention on adenosine signaling, a pathway that clearly has many tricks that remain to be discovered.

Figure 1. Multiple facets of adenosine signaling.

New evidence from Long et al. implicates adenosine as a signaling molecule sensed by cells to trigger cell death. Adenosine is recognized by the ADORA2B receptor (A2BR’), a target of p53. Adenosine signaling induces the upregulation of PUMA and the downregulation of the anti-apoptotic proteins Bcl-2 and Bcl-XL, resulting in apoptosis.