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: [email protected]://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
Previews
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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