The Circadian Clock in Cancer Development and Therapy - Progress in Molecular Biology and Translational Science - page 245

and increases glutamine uptake to compensate for the progressive loss of glu-
cose as a mitochondrial substrate in cancer cells due to theWarburg effect, 291
Myc also upregulates mitochondrial biosynthesis by regulating genes includ-
ing nuclear respiratory factor 1 (NRF1) and the transcription factor A, mito-
chondrial as well as cytochrome C , to stimulate the production of ROS. 292-296
Although elevated ROS leads to Myc -mediated apoptosis in normal somatic
cells, 297 loss of function or deregulation of p53 in combination with Myc
oncogenic activation results in the metabolic switch to support cell prolif-
eration, apoptotic resistance, and neoplastic transformation. 271,298-302
The molecular clock not only controls metabolic homeostasis by regu-
lating nuclear receptors and their coactivators and suppressors as well as
chromatin remodeling in metabolically active peripheral tissues 6,272-275,303
but is also regulated by nuclear receptors REV-ERB a / b , ROR a , and
PPAR g coactivator PGC-1 a , which play an active role in energy metabo-
lism, adipogenesis, and lipid storage in peripheral tissues, and by nutrient
sensors such as AMPK. 8-10,282,304 Therefore, disruption of the molecular
clockworks would inevitably shift the homeostasis of metabolism and energy
balance in peripheral tissues to provide an intracellular environment that
favors tumor initiation and progression.
4.1.4 Control of cell senescence by the molecular clock
Aging is frequently associated with disruption of circadian rhythmicity in
humans and animal models. 305-307 Premature aging is commonly observed
among circadian gene-mutant mouse models. Among them, Bmal1 /
mice display the most aggressive aging phenotypes leading to a significantly
reduced life span. 125 Other circadian gene-mutant mouse models including
mice carrying a mutated Clock ( Clock m/m ) or lacking Per or Cry genes
( Cry1 / ; Cry2 / , Per1 / ; Per2 / , Per2 m/m ,or Per2 / ) also display pre-
mature aging phenotypes, which become more evident in response to DNA
damage agents such as g -radiation. 29,124,128,129 These premature aging phe-
notypes of circadian gene-mutant mouse models are closely related to dereg-
ulation of cell proliferation and DNA damage response in vivo .
Aging is a universal process for all multicell organisms on earth, which is
measured chronologically by biological changes over time and is accompa-
nied by a dramatic increase in the risk of various diseases at the mid-point of
the life span. 308 Although aging is marked by progressive degeneration of
tissue and cell function in vivo , it is also coupled with an increased risk of
neoplastic growth in renewable tissues in mammals, leading to the conclu-
sion that aging is a primary risk factor of cancer. 309,310 The mechanisms