Altered Metabolism in

Cancer Cells
Emily Tieu
NUTR 6440
Background
Cancer is caused by mutations and altered
gene expression resulting in uncontrolled
cell growth
Impaired mitochondrial function and
impaired respiration linked to growth,
division, and expansion of tumor cells
Cancer Cell Metabolism
Normal cells and cancer cells differ in how they derive
energy from glucose
Normal: aerobic
O2 +glucose glycolysis oxidative phosphorylation 38 ATP
Cancer: anaerobic
glucose glycolysis only 2 ATP
Cancer cell glycolysis dependence = Warburg effect
Warburg Effect
Even in the presence of O2, cancer cells
prefer to metabolize glucose through
glycolysis
Glycolysis is a less efficient pathway for
producing ATP, which means cancer cells
need more glucose
Pyruvate kinase and Warburg Effect
Pyruvate kinase involved in last
step of glycolysis
2 different versions:
M1 isoform- expressed in
most adult tissues
M2 isoform- expressed by
tumor tissues
Responsible for
enabling cancer cells to
consume glucose at
faster rate
Identified in all cancer
cells (Cantley, 2008)
Glycolysis vs. Oxidative
Phosphorylation
In cancer, glucose used more for
replication than for normal cell
metabolism
Rapidly growing tumor cells can have
glycolytic rates up to 200 times higher
than normal cells
Thus, cancer cells accumulate more
radioactive material
Metabolism of Proliferating Cells
Normal cells meet energy
demands through FA oxidation
and oxidative metabolism of
glucose
Proliferating cells must satisfy 3
demands:
Bioenergetics
Macromolecular
biosynthesis
Redox homeostasis
Proliferating cells have increased
uptake of glucose and glutamine
(2 primary substrates that fuel
cell growth)
Glucose and Glutamine Fuel
Proliferation
Catabolism of glucose to lactate
allows proliferating cells to shunt
glycolytic intermediates into
anabolic pathways that support
additional metabolic requirements
Glutamine
Nitrogen source for
biosynthesis of nucleotides and
nonessential amino acids
Carbon source for
replenishment of TCA cycle
intermediates
Signaling pathways of proliferating
cells
P13K/Akt and MAPK increase
glycolysis and upregulate SREBP
mTOR activates protein translation,
glycolysis (by enhancing HIF1
activity), and lipogenesis through
SREBP and Myc
HIF1 increases expression of GLUT
and PDK1
Myc upregulates glutamate synthesis,
increases glycolysis and lactate
production
AMPK allows cells to switch to
catabolism when nutrients low
p53 inhibits glycolysis
Metabolic Checkpoint: p53, mTOR,
AMPK
Many tumor cells lack p53
p53 inactivation can lead to Warburg effect
LKB1 absent in many tumor cells
LKB1= AMPK activator
AMPK inactivates mTOR
Thus, mTOR hyperactivated in cancer cells
Glycolysis Activation in the presence of
O2
Increased O2 and H2O2
generation leads to
aerobic glycolysis
H2O2 can activate HIF-1
HIF-1 activates
aerobic glycolysis
and represses
oxidative
phosphorylation
Future Research
The Warburg Effect is only one aspect of
cancer metabolism, the extent of metabolic
differences between cancer and normal cells
is currently not known
Links between metabolism and cell death
and extent of metabolic flexibility unknown
References
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Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL, Cantley
LC (2008). "The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth". Nature
452 (7184): 230233.
Hsu PP and Sabatini DM (2008). Cancer cell metabolism: Warburg and beyond. Cell 134: 703-707.
Pavlides S, Whitaker-Menezes D, Castello-Cros R, FlomenbergN, Witkiewicz AK, Frank PG, Casimiro MC, Wang C,
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