Caffeine and Apoptosis - Caffeine: Chemistry, Analysis, Function and Effects - page 383

be responsible for accelerated cell growth, increased cell survival, and

resistance to genotoxic anticancer agents.
Following DNA damage, p53 has a major influence on whether a cell will
live or die. Cells exposed to DNA-damaging agents such as c-radiation or
many chemotherapeutic agents pause in their cell cycle progression to allow
time for DNA repair. If the damage is too extensive, the affected cells will
undergo apoptosis. Both cell cycle arrest and apoptosis are normally mediated
by p53 activities (Canman et al 1994; Enoch and Norbury 1995). One of the
primary p53 targets is the Bax protein, a member of the Bcl-2 family that
controls cell death through its participation in disruption of mitochondria and
subsequent cytochrome c release (Marzo et al 1998).
In addition, the Ataxia-telangiectasia mutated (ATM) and ATM and
RAD3-related (ATR) pathways play important roles in DNA damage
response and tumor suppression. ATM and ATR belong to the phosphoinosi-
tide 3-kinase (PI3K)-related protein kinases (PIKKs). ATM responds
primarily to double-strand breaks (DSBs) induced by ionizing radiation, while
ATR reacts to UV or stalled replication forks. The list of ATR and ATM
substrates is rapidly expanding; however, the best studied is the Ser-Thr kinase
checkpoint kinase-1 (Chk1). Chk1 kinase is an important effector and
substrate of ATR; it plays a key role in mediating replication fork stability
following DNA damage and is also required for cell cycle checkpoint
activation (Chen and Sanchez 2004). ATM activates another checkpoint
protein, checkpoint kinase-2 (Chk2). These pathways coordinate the DNA
damage checkpoint function and apoptosis. Defects in the ATR-Chk1 and
ATM-Chk2 pathways increase cancer risk.
Another protein that is critical for tumorigenesis through regulating cell
survival and growth is the serine-threonine kinase AKT, also known as protein
kinase B. AKT is a downstream effector of phosphatidylinositol 3-kinase
(PI3K) that has recently been a focus of intense research. It appears that AKT
lies at the cross-roads of multiple cellular signaling pathways and acts as a
transducer of many functions initiated by growth factors and other receptors
that activate PI3K. One of the major activities of AKT is to promote cell
survival. AKT is activated in response to UVB irradiation and is frequently
activated in human cancers (Bode and Dong 2003; Bowden 2004; Ming et al
2010).
In this review, we will focus on the mechanistic action of caffeine on
apoptosis via the p53, ATR-Chk1 and AKT-COX-2 pathways, respectively.
We hope to establish the relationship between apoptosis and caffeine as a
framework for a more general understanding of the function of caffeine.

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21.2 Caffeine and p53
In serum-starved JB6 CL41 cells containing wild-type p53, caffeine induces
apoptosis through p53, Bax, and caspase 3; in p53(-/-) fibroblast cells, caffeine
did not enhance apoptosis (He et al 2003) (Figure 21.1). Both phosphorylation