Editors' ChoiceCell Biology

Primed to Die

Science Signaling  14 May 2013:
Vol. 6, Issue 275, pp. ec108
DOI: 10.1126/scisignal.2004320

The adenosine 2B (A2B) receptor is a low-affinity receptor for adenosine, a metabolic product that accumulates in cells with increased energy consumption or in response to nutrient or oxygen deprivation, conditions associated with cancer cells. Long et al. found that the gene encoding A2B was a transcriptional target of tumor suppressor p53, which stimulates cell cycle arrest or cell death through apoptosis in response to various forms of cellular stress. Cells in which A2B was increased, either through transfection or p53-mediated induction, exhibited increased caspase-dependent cell death in response to an analog of adenosine. Cells transfected with A2B exhibited increased cell death in response to hypoxia, and this was associated with an increase in adenosine concentration in the medium. Cells transformed in culture exhibited p53-dependent induction of A2B and, in response to the chemotherapeutic agent cisplatin, adenosine in the medium increased and A2B-dependent cell death occurred. Assays to detect changes in the abundance of various anti- or proapoptotic proteins, combined with inhibitor studies and overexpression and deficiency studies, indicated that A2B signaling resulted in a reduction in the antiapoptotic proteins Bcl-2 and Bcl-XL (or Mcl-1, depending on the cell type) and an increase in the proapoptotic protein Puma, which antagonizes the Bcl-2 family members. Thus, these results suggest that by inducing the production of A2B, p53 primes cells to undergo death in response to metabolic changes associated with cancer or chemotherapy.

J. S. Long, D. Crighton, J. O’Prey, G. MacKay, L. Zheng, T. M. Palmer, E. Gottlieb, K. M. Ryan, Extracellular adenosine sensing—A metabolic cell death priming mechanism downstream of p53. Mol. Cell 50, 394–406 (2013). [PubMed]

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