The Circadian Clock in Cancer Development and Therapy - Progress in Molecular Biology and Translational Science - page 229

Deregulation of the core circadian genes in human cancers is closely
associated with a constitutive activation of intracellular inflammatory and
oncogenic signaling pathways including the constitutive activation of
p38, c-MYC, NF- k B, BCL-XL, and protein kinase A (PKA ) 66,75,79,98,106 ;
aberrant chromatin remodeling; deregulation of inflammatory cytokines,
catalase, TIP60, telomerase, PARP [poly (ADP-ribose) polymerase], SIRT1
and p300 66,67,75,105-107 ; overexpression of ER a , G1, and S-phase cyclins;
and suppression of tumor suppressors, ATM, p53, p21 WAF1/CPI1 , and
WEE1. 68,69,79,82,92 Deregulation of the molecular clock is correlated with
the loss of control in cell proliferation, metabolism, DNA replication
and repair, senescence, apoptosis, and DNA damage response, and increased
drug

resistance in all types of human cancer cells studied

( Table 9.1 ). 67,68,70-75,79,82,83,92,95,97,98

2.4. Central clock dysfunction increases cancer risk in humans
In the hierarchical organization of the mammalian circadian clock, the periph-
eral clock can only sense changes in environmental light cues via central clock-
controlled circadian output pathways. Thus, central clock dysfunction induced
by frequent back-and-forth phase shifts of environmental cues may play a key
role in promoting cancer development among human night-shift workers by
disrupting the homeostasis of neuroendocrine function. 107-110 This hypothesis
is supported by the facts that visually impaired people who are insensitive to
changes in environmental circadian light cues and largelyor completelydepend
on a free-running endogenous clock toorganize their daily physiology display a
lower cancer risk compared to the general population. 111-113
In summary, ample evidence obtained from human studies suggests that
the mammalian circadian clock plays a key role in tumor suppression.
Therefore, disruption of circadian homeostasis of mammalian physiology
is a novel risk factor for cancer ( Table 9.1 ).

3. CIRCADIAN DISRUPTION PROMOTES CANCER
DEVELOPMENT IN ANIMAL MODELS
3.1. The central clock suppresses tumor initiation and
progression in animal models
Pioneering studies to investigate the role of circadian disruption in cancer
development using experimental animal models started in the late 1960s.
These studies demonstrate that disruption of circadian endocrine rhythms