2. METABOLIC DIFFERENCES BETWEEN
NORMAL & CANCER CELLS
Normal cells do not metabolize glucose to lactate when
oxygen is available. Only when the oxygen is absent or
limiting do normal cells resort to anaerobic glycolysis or
metabolism of glucose to lactic acid.
Cancer cells metabolize glucose to lactate even in the
presence of oxygen (aerobic glycolysis). The idea that
cancer cells exhibit an altered metabolism was given by
Otto Warburg.
3. INTRODUCTION OF WARBURG EFFECT
WARBURG EFFECT Usually, cancer cells are highly
glycolytic (glucose addiction) and take up more glucose
than do normal cells from outside.
Otto Heinrich Warburg (; 8 October 1883 – 1 August 1970)
In 1931 was awarded the Nobel Prize in Physiology for his
"discovery of the nature and mode of action of the
respiratory enzyme.
4. WARNBURG EFFECT
Cancer cells under aerobic (well-oxygenated) conditions to
metabolize glucose to lactate (aerobic glycolysis) is known as
the Warburg effect.
Warburg made the seminal observation that tumor slices
consume glucose and secrete lactate at a higher rate than
normal tissues, even in the presence of air (aerobic conditions)
& Normal cells rely on mitochondrial oxidative
phosphorylation to produce ATP.
5. Under aerobic conditions, normal cells and tissues
metabolize glucose to carbon dioxide (CO2) and water
(H2O) through oxidative phosphorylation and convert
glucose to lactate (glycolysis) under hypoxic (poorly
oxygenated) conditions.
However, tumor tissues metabolize glucose to lactate even
under aerobic conditions. Most cancer cells depend on
glycolysis, even in the presence of plenty of oxygen, to
generate a considerably lesser amount of ATP with a
decreased use of the oxidative phosphorylation mechanism.
6. GLYCOLYSIS / TCA CYCLE
Pyruvate is the critical metabolite of the glycolytic
pathway.
It is responsible for the formation of lactic acid catalyzed
by lactate dehydrogenase (LDH) in cancer cells.
Alternatively, pyruvate can enter into the Krebs cycle.
Important regulators of the TCA cycle that are formed from
citric acid are alpha-ketoglutarate formed from isocitrate,
succinate from succinyl-COA , fumarate and malonate, and
ultimately oxaloacetate that combines with acetyl-COA to
keep the TCA cycle going.
7. GLUTAMINOLYSIS
Cancer cells also take up and metabolize glutamine To
sustain the functioning of the TCA uninterruptedly,
metabolites can be fed into this cycle.
V-Ki-ras2 Kirsten rat sarcoma (KRAS), the viral
oncogene stimulates cancer cell growth through enhanced
formation of alpha-ketoglutarate via the TCA cycle and
Increased the activity of the enzyme, glutamate pyruvate
transaminase, was observed in cancer Thus,
glutamine/glutamate metabolism provides an attractive
therapeutic target.
8. ROLE OF MITOCHONDRIA IN CANCER
METABOLISM
Warburg hypothesized that cancer cell mitochondria are
dysfunctional, thus forcing the cells depends upon
exclusively on glycolysis for energy.
The functional role of mitochondria in tumor cells
became clearer when cancer cells treated with
mitochondria- targeted compounds showed repressed
respiration, decreased cell proliferation, and ATP
formation.
9. Activation of glycolysis and inhibition of
the mitochondria in cancer
Glucose
Pyruvate
PDC
Acetyl-CoA
CAC
CO2
ATP
Mitochondrion
Lactate
― + H+
Tumor
10. REVERSE WARBURG EFFECT
The glycolytic product, lactic acid, secreted by cancer
cells or fibroblasts is also used by neighboring cancer
cells to make citric acid and sustain cancer progression.
The “reverse Warburg effect” is a new term for “parasitic”
cancer metabolism. It was proposed that cancer cells act
as metabolic parasites in that they obtain nutrients from
host cells by inducing catabolic processes. One such
process is aerobic glycolysis in host cells.
11. INHIBITING GLYCOLYSIS AS A
POTENTIAL ANTI TUMOR STRATEGY
Glucose is one of the most abundant sources of energy in
cancer cells.
During the breakdown of one molecule of glucose in the
presence of oxygen, six molecules of carbon dioxide and
water are released in addition to energy in the form of
ATPs. Nearly 34–38 ATP molecules are produced during
glycolysis, the Krebs cycle, and mitochondrial respiration .
If targeting glycolytic and mitochondrial metabolism is a
strategic approach to slow or inhibit the growth of cancer
cells.
12. INHIBITING GLUCOSE UPTAKE
Glucose uptake into cancer cells is the rate-limiting step in
glycolysis targeting GLUTs(a family of membrane-bound
proteins called GLUTs) by blocking their glucose transport
channel with small molecules should be a viable
mechanism of nutrient deprivation in tumors.
Currently, there exist several GLUT inhibitors, including
cytochalasin B and selected tyrosine kinase inhibitors.
Some of these compounds are relatively less toxic to
normal cells, showing promise in tumor treatment.
13. TARGETING PYRUVATE OXIDATION
Pyruvate is viewed as a “hub” metabolite (being at the
interface of glycolysis and mitochondrial metabolism) in
cell metabolism and especially plays a central role in
regulating metabolic reprogramming in cancer cells.
14. CAN NORMAL CELL METABOLISM CAUSE
CANCER?
Normal metabolism produces reactive oxygen species
(ROS)
ROS can induce cancer
Multiple changes in gene expression are
responsible for aerobic glycolysis in cancer cells
Inactivation of p53
Activation of HIF-1
15. ROLE OF HIF-1 & P53 IN CANCER CELL
HIF-1 is activated in many cancers.
Increase in HIF-1 induces the same effects as loss of p53
function, i.e. causes greater glycolytic flux, reduced
pyruvate oxidation, and reduced production of ATP by
oxidative phosphorylation.
Therefore, because of increase in HIF-1 and decrease in
p53, many tumors use “aerobic” glycolysis as their major
energy pathway.
16. PRODUCTION OF ROS BY MITOCHONDRIA
Generation of mitochondrial ROS mainly takes place at
the electron transport chain located on the inner
mitochondrial membrane during the process of oxidative
phosphorylation.
Leakage of electrons at complex I and complex III from
electron transport chains leads to partial reduction of
oxygen to form superoxide.
17.
18. WHAT PURPOSE DOES ALTERED METABOLISM
SERVE IN CANCER CELLS?/ CONSEQUENCES.
Assures ATP synthesis when tumor outgrows its oxygen
supply.
Assures supply of building blocks for proliferation and
growth.
Creates space by starving neighboring cells for nutrients
Release of acid lowers extracellular which favors tumor
invasion and suppresses immune effectors.
Increases resistance to oxidative stress by promoting
NADPH production and reduction of glutathione.
Reduces production of reactive oxygen species (ROS) by
mitochondria.
19. SUMMARY OF NORMAL CELL METABOLISM &
CANCER CELL METABOLISM
The metabolism of glucose and glutamine by normal
cells is very efficient. Primary end products are CO2,
H2O, and ammonia (or urea). Maximum ATP yield per
mole of glucose and glutamine is achieved.
The metabolism of glucose and glutamine by cancer cells
is very wasteful. Primary end products are CO2, H2O,
lactate, pyruvate, alanine, and aspartate. Maximum ATP
yield per mole of glucose and glutamine is not achieved.
20. FUTURE PROSPECTS
Recent research implicates that mitochondrial
metabolism is vital for tumor growth Targeting
mitochondrial metabolism is an emerging area of
research in cancer biology. Cancer cell mitochondrial
membrane potential is much more negative than normal
cell mitochondria.
