Molecular Cell

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Adenosine: Essential for Life but Licensed to Kill

Vivian Gama1,2 and Mohanish Deshmukh1,2,*1Neuroscience Center2Department of Cell Biology and PhysiologyUniversity of North Carolina, Chapel Hill, NC 27599, USA*Correspondence: mohanish@med.unc.eduhttp://dx.doi.org/10.1016/j.molcel.2013.04.020

In this issue ofMolecular Cell, Long and Crighton (2013) report a cell death priming mechanism activated byp53 that senses extracellular adenosine accumulated following chemotherapy or hypoxia, providing a novelconnection between adenosine signaling and apoptosis.

Figure 1. Multiple Facets of AdenosineSignalingNew evidence from Long and Crighton (2013)implicates adenosine as a signaling moleculesensed by cells to trigger cell death. Adenosine isrecognized by the ADORA2B receptor (A2BR’), atarget of p53. Adenosine signaling induces theupregulation of PUMA and the downregulation ofthe anti-apoptotic proteins Bcl-2 and Bcl-XL,resulting in 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.

(1970) described the release of extracel-

lular ATP by nonadrenergic inhibitory

nerves, purinergic signaling is now a

widely accepted concept and an

increasing area of investigation. For

example, extracellular ATP and adeno-

sine, the metabolite generated from the

breakdown of ATP by ecto-nucleotid-

ases, have been implicated as signaling

molecules in a broad range of cellular

pathways including pain, taste, phagocy-

tosis, and angiogenesis (Elliott et al.,

2009; Gessi et al., 2011; Sawynok and

Liu, 2003). In this issue of Molecular Cell,

Long and Crighton (2013) report the

surprising observation that adenosine

signaling is also linked to chemotherapy-

induced apoptosis.

The extracellular concentration of

adenosine is constant under basal condi-

tions in most tissues, but it can rapidly in-

crease almost 100-fold in hypoxic tissue

and in response to inflammation (Fred-

holm, 2007; Stagg and Smyth, 2010).

Not surprisingly, adenosine accumulates

in the extracellular tissue surrounding

tumors because the tumor microenviron-

ment 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 implica-

tions of an adenosine-sensing mecha-

nism in cancer have been unclear. Long

and Crighton (2013) shed light onto this

unknown mechanism. The authors iden-

tify the adenosine receptor, ADORA2B

(A2B), as a direct p53 target gene

(Figure 1). Importantly, they demonstrate

that an apoptotic program is triggered

under conditions in which extracellular

adenosine accumulates and p53 induces

A2B expression.

Long and Crighton (2013) 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 nongenotoxic stimuli

(e.g., methotrexate) induce A2B expres-

sion. These studies also revealed that

treatment with cisplatin not only induced

p53-dependent expression of endoge-

nous 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 pro-

duction 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 extra-

cellular 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 regu-

Molecular Ce

lated 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

ll 50, May 9, 2013 ª2013 Elsevier Inc. 307

Molecular Cell

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Youle, 2011). Long and Crighton (2013)

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 adeno-

sine signaling and the p53 tumor suppres-

sor pathway. In addition, these results

imply that cells possess a unique

signaling pathway capable of sensing tu-

mor-associated metabolic changes in

the microenvironment and eliminating

the transformed cells.

The findings by Long and Crighton

(2013) add 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

308 Molecular Cell 50, May 9, 2013 ª2013 El

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 unex-

plored. It would also be interesting to

determine whether inactivation of adeno-

sine secretion or signaling is associated

with the development of chemoresist-

ance. Importantly, experiments probing

the role of the adenosine signaling

pathway in in vivo models will shed light

on its role in tumorigenesis and associa-

tion with chemoresistance. This research

by Long and Crighton (2013) indeed pro-

vides a new perspective for the develop-

ment 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.

sevier Inc.

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