The Circadian Clock in Cancer Development and Therapy - Progress in Molecular Biology and Translational Science - page 246

linking aging to cancer include immunosenescence and age-related endo-
crine dysfunction at the organismal level as well as telomere shortening,
reproductive cell cycle, and accumulation of DNA damage over a life-
time. 311-316 These adverse age-related pathological changes have led to
the conclusions that if humans live long enough, they would all eventually
develop cancer. 317,318
Throughout the life span, mammals need continuous cell proliferation to
support their daily physiology. However, the inherent limitations in DNA
repair mechanisms inevitably lead to accumulation of errors in genomic
DNA, which often results in replicative or cellular senescence, a direct cause
of aging. 319-323 Senescence refers to a state of permanent and irreversible with-
drawal from the cell cycle resulting from accumulation of cellular damages
includingDNA lesions, oncogenic activation, and/or overexpression of tumor
suppressors. 157 Since cancer cells do not have a limited replicative life span, cel-
lular senescence is often used to enforce the idea that it suppresses cancer devel-
opment. 324 However,mounting evidence suggests that cellular senescence also
promotes cancer initiation and progression. Senescent cells are still metaboli-
cally active andoften showchanges in chromatinorganization andgene expres-
sion, leading to secretion of proinflammatory cytokines, proteases, and growth
factors. The paracrine activities of senescent cells have been found to stimulate
proliferation andmigration of neighboring cells and promote the development
ofmetastatic tumors. 325-328 The activation of Myc , Ras/MAPKoncogenic sig-
naling and/or p53/p21 WAF1/CIP1 , and pRB/p16 INK4a tumor suppressingpath-
ways are established molecular mechanisms for cellular senescence. 329-332
Under certain conditions, suppression or even a subtle change in the expression
of these tumor suppressors could lead to senescent cells to rapidly regain the abil-
ity to proliferate. 333
Increased oxidative stress in circadian gene-mutant mice may lead to a
higher level of accumulation of DNA damage that induces early cellular
senescence to promote aging. 125,306,334 The modulators of the molecular
clock, such as NAD-dependent deacetylase sirtuin-1 (SIRT1), may play a
role in bridging the aging and cancer-prone phenotypes found in circadian
gene-mutant mice. 6 SIRT1 is a class III histone deacetylase that promotes
cell survival by inhibiting apoptosis and cellular senescence in mammals. 335
SIRT1 expression follows a robust circadian expression in vivo .Itdirectly
interacts with CLOCK and deacetylates BMAL1 to regulate the activity of
the molecular clock, 12,13 and also plays a role in regulating cell proliferation
and apoptosis by deacetylating key tumor suppressors and oncoproteins
including p53, b -Catenin, and DNA repair protein KU70. 336-338 Both Bmal1