The Circadian Clock in Cancer Development and Therapy - Progress in Molecular Biology and Translational Science - page 244

4.1.3 Control of cell metabolism by the molecular clock
Cancer is classically considered as a disease originated from genetic and epi-
genetic abnormalities that lead to uncontrolled cell growth and division, and
formation of metastasizing tumors. The prevalence of metabolic syndromes
worldwide and its coherence to cancer has led to a renewed interest in the
Warburg effect, which describes an essential role of deregulation of cell
metabolism in cancer initiation. In 1956, Otto Warburg observed that nor-
mal quiescent somatic cells metabolize glucose to CO 2 and H 2 O via a low
rate of glycolysis followed by oxidation of pyruvate in TCA cycle in mito-
chondria. However, cancer cells predominantly use glucose to produce
energy through a high rate of glycolysis followed by lactic acid fermentation
in the cytosol even in the presence of abundance oxygen. Warburg
predicted that this metabolic reprogram is a fundamental cause of cancer. 262
Studies in the past decade have revealed that cancer cells display an array of
metabolic abnormalities and that both oncoproteins and tumor suppressors
can influence the switch between aerobic glycolysis and the use of TCA
cycle to generate ATP. 263-268 The predominant use of the aerobic glycolysis
pathway in cancer cells leads to not only a high level of intracellular ROS, a
major source of endogenous DNA damage agents promoting cancer and
aging, but also the accumulation of intermediate products including purines,
pyrimidines, nonessential amino acids, and free fatty acids that can be used
for anabolic synthesis, cell growth, and division. 266,269-271
The mammalian circadian clock is a master regulator of metabolic
homeostasis both at the organismal and peripheral tissue levels. 6,272-275 In
peripheral tissues, the molecular clock regulates nutrient uptake, metabo-
lism, energy storage, mitochondria biosynthesis, and intracellular redox
levels by targeting key metabolic genes including those controlling the War-
burg effect, such as glucose-6-phosphatase, pyruvate kinase, and glucose
transporter 2 (GLUT). 17,20,198,276,277 It also responds to food cues and nutri-
ent sensors to shift metabolic balance independent of SCN clock func-
tion. 12,278-283 The peripheral clock also indirectly controls Warburg
switch by regulating the expression of oncoproteins and tumor suppressors.
For example, p53 inhibits aerobic glycolysis and decreases intracellular ROS
levels by suppressing GLUT1-4 and fructose-2,6-bisphosphate, a critical
substrate of aerobic glycolysis, via the tumor suppressor p53-induced glycol-
ysis and apoptosis regulator, 284,285 and promotes the use of the TCA cycle by
inhibiting glycolic enzyme phosphoglycerol mutatase. 286 Whereas c-MYC
stimulates biosynthesis to support cell growth and proliferation via
upregulation of lipogenetic, glycolytic, and mitochondrial genes, 287-290