Abstract
p53 primes cells for extracellular adenosine-induced death by inducing adenosine receptor A2B.
Major finding: p53 primes cells for extracellular adenosine-induced death by inducing adenosine receptor A2B.
Clinical relevance: Hypoxia and chemotherapy increase extracellular adenosine and A2B-dependent cell death.
Impact: A2B provides a link between the roles of p53 in regulating metabolism and programmed cell death.
In addition to its well-established role in the regulation of cell death, increasing evidence suggests that p53 regulates cellular metabolism by activating the expression of genes involved in various metabolic pathways. It is unknown whether these are independent functions of p53, or if there are p53 target genes that link metabolic changes to programmed cell death. Long and colleagues screened expression data for p53-inducible targets with possible roles in sensing metabolic changes and validated ADORA2B, which encodes the adenosine receptor A2B, as a direct p53 target gene. A2B is a member of a family of transmembrane G protein–coupled receptors that are activated by adenosine produced from the breakdown of ATP. A2B has a much lower adenosine affinity compared with the other adenosine receptors and is thought to be activated only by abnormally high levels of extracellular adenosine accumulation caused by metabolic stressors such as nutrient depletion and oxygen deprivation.
Interestingly, treatment of transformed cells with an adenosine analogue induced apoptosis in an A2B-dependent manner, with A2B signaling resulting in induction of a caspase-dependent apoptotic pathway in association with downregulation of the antiapoptotic proteins BCL-2 and BCL-XL and upregulation of the proapoptotic protein PUMA. The authors also observed A2B -dependent cell death in cancer cells expressing A2B grown under hypoxic conditions, consistent with a model in which p53-dependent induction of ADORA2B expression sensitizes cells to stress conditions that generate extracellular adenosine. Surprisingly, cisplatin, which is thought to induce cell death through a p53-dependent DNA damage response, also significantly increased extracellular adenosine levels and induced A2B-dependent cell death in transformed cells. Together, these findings uncover a mode of p53-dependent apoptosis linked to metabolic stress that may potentially be exploited to induce cancer cell death.
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