A German biochemist, Dr. Otto Warburg showed in 1928 that tumor cells have a higher rate of glucose metabolism. ▫ He showed that tumor cells convert ten times more glucose into lactate into glucose (in a given time), under aerobic conditions. ▫ It is said to be an adaptation of cancer cells, to counter the variability in energy demand with time. They show high glycolytic metabolism even with oxygen present.

1. Glycolytic Activity of
Cancer Cells

2. Overview of the Glycolytic pathway
▫ Glycolysis is a metabolic processes responsible for glucose
degradation.
▫ In glycolysis, the breakdown of glucose molecules generates two net
adenosine triphosphate (ATP) molecules, which provide a readily
available source of energy for various reactions in the cell, and two
pyruvate molecules, which can be converted into lactate, acetyl-
CoA, oxaloacetate and alanine.
▫ Glycolysis, which occurs exclusively in the cytoplasm, is the sole
source of ATP in cells that lack mitochondria (e.g., red blood cells).

3. In normal body cells, in the presence of oxygen, the pyruvate produced
enters TCA and ETC. In anaerobic conditions it becomes lactate.

4. The Warburg Effect
▫ A German biochemist, Dr. Otto Warburg showed in 1928 that
tumor cells have a higher rate of glucose metabolism.
▫ He showed that tumor cells convert ten times more glucose
into lactate into glucose (in a given time), under aerobic
conditions.
▫ It is said to be an adaptation of cancer cells, to counter the
variability in energy demand with time. They show high
glycolytic metabolism even with oxygen present.

5. ▫ As well as tumor cells, other
proliferative cells (when
normal growth of tissues
occurs) also show Warburg
effect.

6. Efficiency
of anaerobic and
aerobic glycolysis
both, is much less
than oxidative
phosphorylation.

7. Role of Warburg effect in Tumor cells
▫ As tumors do not have a capillary network initially, the tumor
tissue undergoes hypoxia.
▫ As cancer cells are growing FAST, they require more energy.
Because of this thirst for energy glucose uses a inefficient
pathway to generate considerate amount of energy.

8. Role of Pyruvate Kinase in Cancer
▫ Cancer cells express a special isoform of pyruvate kinase called
PKM2, a splicing variant of the muscle form of pyruvate kinase
(PKMl) .
▫ PKM2 is required for rapid growth of tumor cells. Although PKMl
and PKM2 are closely related, PKMl cannot substitute for PKM2
in cancer cells.
▫ Why tumors require this specific pyruvate kinase isoform is still
being investigated.

9. ▫ All cancer cells express PKM2, an
isoform of pyruvate kinase seen in
embryos but not in normal adult
tissues. For reasons chat are not
understood, the exceptional
capacity chat cancer cells have for
aerobic glycolysis depends on chis
particular isoform of pyruvate
kinase.
▫ Aerobic glycolysis by cancer cells, discovered
by Otto Warburg, the recipient of the 1931
Nobel Prize for Physiology and Medicine,
refers to an unusually rapid race of glycolysis
and overproduction of lactate in the presence
of oxygen.
▫ Noncancerous cells extract more ATP per
glucose, and therefore use less glucose and
produce little or no lactate when oxygen is
present.
Pyruvate Kinase M2
[PKM2]

10. ▫ This is because
the rate of glycolysis is
rightly coordinated
with the rates of the TCA
cycle and oxidative
phosphorylation in normal
cells
▫ In cancer cells glycolysis
exceeds the capacity for
complete glucose
oxidation, resulting in
overproduction of lactic
acid, in spite
of the presence of oxygen

11. ▫ Warburg proposed that the replacement of respiration
by fermentation is the primary cause of cancer.
▫ Subsequent research has shown this is not the case. Cancer is
caused by mutations that activate proto-oncogenes and inhibit
rumor suppressor genes.
▫ Nevertheless, altered expression of genes encoding PDKM2 and
other enzymes that increase the capacity for glycolysis provide
cancer cells with a survival and growth advantage over non-
cancer cells.

12. What causes the Warburg effect?
▫ Hypoxia – Possible adaptation made to overcome the lack of
oxygen in the tumor’s environment.
▫ Mitochondrial defects – Mutations in mitochondrial DNA could
lead to malfunctions in respiration and oxidative
phosphorylation.
▫ Oncogenic signals – Point Mutations in genes such as RAS
family can result in cell proliferation & signal initiation.
▫ Altered metabolic enzymes – Overproduction & mimicking of
metabolic enzymes such as Hexokinase II could result in
increased glycolytic activity.

13. Suppression of tumor by blocking glycolysis
▫ There have been several researches that explore the possibility of
reducing tumor growth by inhibiting the glycolytic pathway of these
glucose-hungry tumor cells.
▫ The identification of new therapies that kill tumor cells while sparing
healthy tissues is still a major challenge of cancer research.
▫ In fact, over the past few years, a first series of anti-glycolytic
agents have entered clinical trials (Table in next slide) and many others
are expected to follow them in the near future. So far, the glycolytic
targets that have been considered for clinical studies can only be
found either at the top of the glycolytic flux, such as GLUTs.

14. Principal clinical trials of compounds targeting tumor glyclysis