Use slideshow after downloading for better viewing. The slides cover altered metabolism in cancer with a focus on Warburg effect and drug targeting of metabolic pathways for cancer treatment.
Prepared in Oct 2014
Use slideshow after downloading for better viewing. The slides cover altered metabolism in cancer with a focus on Warburg effect and drug targeting of metabolic pathways for cancer treatment.
Prepared in Oct 2014
Emerging evidence indicates that impaired cellular energy metabolism is the defining characteristic of nearly all cancers regardless of cellular or tissue origin. In contrast to normal cells, which derive most of their usable energy from oxidative phosphorylation, most cancer cells become heavily dependent on substrate level phosphorylation to meet energy demands. Evidence is reviewed supporting a general hypothesis that genomic instability and essentially all hallmarks of cancer, including anaerobic glycolysis (Warburg effect), can be linked to impaired mitochondrial function and energy metabolism. A view of cancer as primarily a metabolic disease and how Autophagy process is activated will impact approaches to cancer management and prevention
ellular respiration describes the series of steps that cells use to break down sugar and other chemicals to get the energy we need to function. Energy is stored in the bonds of glucose (like a stretched rubber band), and when glucose is broken down, much of that energy is released. Some of it is captured in a form that can be used to do work in cells - a molecule called adenosine triphosphate or ATP. The energy that is not captured in ATP is usually given off as heat (one of the things that helps us maintain our normal body temperature).
The process of cellular respiration is similar to a car using gasoline as fuel. As gasoline is the fuel for a car, glucose is the fuel for a cell. A car burns gasoline and uses the energy released for movement. Similarly, a cell ‘burns’ glucose to capture the energy and create ATP. ATP is the primary form of energy that cells use to function.
The first step of respiration is called glycolysis. In a series of steps, glycolysis breaks glucose into two smaller molecules - a chemical called pyruvate. A small amount of ATP is also formed during this process. The process can be likened to a waterslide. A person has more energy at the top and loses it as they slide down.
Most healthy cells continue the breakdown in a second process, called the Kreb's cycle. The Kreb's cycle allows cells to “burn” the pyruvates made in glycolysis to get more ATP.
Cellular Signaling Pathways have direct implications on our understanding of tumor cell behavior. A general overview is presented here followed by a brief discussion of some of the major pathways currently implicated in cancer progression : Ras/RAF/MAP kinase pathway and PI3K/AKT/mTOR pathway s
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.
Cell within a tumor that possess the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that comprise the tumor”.
“CSC can thus only be defined experimentally by their ability to recapitulate the generation of a continuously growing tumor”.
Mitochondria are double membranous organelle, the inner membrane is more larger than the outer one. For this reason the inner membrane of the mitochondria folds inside forming a special figure called creasteae. The inner mitochondrial membrane (IMM) contains the subunits for oxidative phosphorylation (OXPHOS). And this inner mitochondrial membrane coverd by a second membrane called the outer mitochondrial membrane (OMM). We called mitochondria as a power house of cell not only they generates ATP via oxidative phosphorylation they also take part in various biochemical pathways such as- pyrimidine and purine biosynthesis, heme biosynthesis, the regulation of N2 balance in urea cycle, gluconeogenesis, keton body production and fatty acid degradation and elongation. They also take part in cell signalling via regulating the protein-protein interaction or by regulating the cellular concentration of calcium ion(Ca2+) and reactive oxygen species(ROS).
During various biological diseasesmitochondrial morphology altered, as in the case when there is lack of nutrient in our body mitochondria combine together to share their nutrient and alo their DNA and ETC components to maintain their OXPHOS. But in case of high energy demand of a part of body mitochondria undergo division or called fission because they move rapidly than lager one (Zhao et al., 2013). Fission also occur in mitotic cell to share equal amount of mitochondria to the daughter cells. Many questions arise in mitochondrial dinamics but here I am going to answer a most doubtful question- Is mitochondrial dynamics play any role in tumorigenic process? Is any oncogenic signalling play crucial role in morphological alteration of mitochondria?
Emerging evidence indicates that impaired cellular energy metabolism is the defining characteristic of nearly all cancers regardless of cellular or tissue origin. In contrast to normal cells, which derive most of their usable energy from oxidative phosphorylation, most cancer cells become heavily dependent on substrate level phosphorylation to meet energy demands. Evidence is reviewed supporting a general hypothesis that genomic instability and essentially all hallmarks of cancer, including anaerobic glycolysis (Warburg effect), can be linked to impaired mitochondrial function and energy metabolism. A view of cancer as primarily a metabolic disease and how Autophagy process is activated will impact approaches to cancer management and prevention
ellular respiration describes the series of steps that cells use to break down sugar and other chemicals to get the energy we need to function. Energy is stored in the bonds of glucose (like a stretched rubber band), and when glucose is broken down, much of that energy is released. Some of it is captured in a form that can be used to do work in cells - a molecule called adenosine triphosphate or ATP. The energy that is not captured in ATP is usually given off as heat (one of the things that helps us maintain our normal body temperature).
The process of cellular respiration is similar to a car using gasoline as fuel. As gasoline is the fuel for a car, glucose is the fuel for a cell. A car burns gasoline and uses the energy released for movement. Similarly, a cell ‘burns’ glucose to capture the energy and create ATP. ATP is the primary form of energy that cells use to function.
The first step of respiration is called glycolysis. In a series of steps, glycolysis breaks glucose into two smaller molecules - a chemical called pyruvate. A small amount of ATP is also formed during this process. The process can be likened to a waterslide. A person has more energy at the top and loses it as they slide down.
Most healthy cells continue the breakdown in a second process, called the Kreb's cycle. The Kreb's cycle allows cells to “burn” the pyruvates made in glycolysis to get more ATP.
Cellular Signaling Pathways have direct implications on our understanding of tumor cell behavior. A general overview is presented here followed by a brief discussion of some of the major pathways currently implicated in cancer progression : Ras/RAF/MAP kinase pathway and PI3K/AKT/mTOR pathway s
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.
Cell within a tumor that possess the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that comprise the tumor”.
“CSC can thus only be defined experimentally by their ability to recapitulate the generation of a continuously growing tumor”.
Mitochondria are double membranous organelle, the inner membrane is more larger than the outer one. For this reason the inner membrane of the mitochondria folds inside forming a special figure called creasteae. The inner mitochondrial membrane (IMM) contains the subunits for oxidative phosphorylation (OXPHOS). And this inner mitochondrial membrane coverd by a second membrane called the outer mitochondrial membrane (OMM). We called mitochondria as a power house of cell not only they generates ATP via oxidative phosphorylation they also take part in various biochemical pathways such as- pyrimidine and purine biosynthesis, heme biosynthesis, the regulation of N2 balance in urea cycle, gluconeogenesis, keton body production and fatty acid degradation and elongation. They also take part in cell signalling via regulating the protein-protein interaction or by regulating the cellular concentration of calcium ion(Ca2+) and reactive oxygen species(ROS).
During various biological diseasesmitochondrial morphology altered, as in the case when there is lack of nutrient in our body mitochondria combine together to share their nutrient and alo their DNA and ETC components to maintain their OXPHOS. But in case of high energy demand of a part of body mitochondria undergo division or called fission because they move rapidly than lager one (Zhao et al., 2013). Fission also occur in mitotic cell to share equal amount of mitochondria to the daughter cells. Many questions arise in mitochondrial dinamics but here I am going to answer a most doubtful question- Is mitochondrial dynamics play any role in tumorigenic process? Is any oncogenic signalling play crucial role in morphological alteration of mitochondria?
The prime cause and treatment of cancer somayeh zaminpira - sorush niknamianbanafsheh61
This meta-analysis research has gone through more than 200 studies from 1934 to 2016 to find the differences and similarities in cancer cells, mostly the cause. The most important difference between normal cells and cancer cells is how they respire. Normal cells use the sophisticated process of respiration to efficiently turn any kind of nutrient that is fat, carbohydrate or protein into high amounts of energy in the form of ATP. This process requires oxygen and breaks food down completely into harmless carbon dioxide and water. Cancer cells use a primitive process of fermentation to inefficiently turn either glucose from carbohydrates or the amino acid glutamine from protein into small quantities of energy in the form of ATP. This process does not require oxygen, and only partially breaks down food molecules into lactic acid and ammonia, which are toxic waste products. The most important result is that fatty acids or better told fats cannot be fermented by cells. This research mentions the role of ROS and inflammation in causing mitochondrial damage and answers the most important questions behind cancer cause and mentions some beneficial methods in preventing and treatment of cancer.
Deciphering Cellular Respiration: Stages, Mechanisms, and Implications | The ...The Lifesciences Magazine
Explore the intricate world of cellular respiration, from glycolysis to oxidative phosphorylation. Understand the regulatory mechanisms, adaptations, and implications of this essential process, including its role in diseases.
Cancer cell metabolism: special Reference to Lactate PathwayAADYARAJPANDEY1
Normal Cell Metabolism:
Cellular respiration describes the series of steps that cells use to break down sugar and other chemicals to get the energy we need to function.
Energy is stored in the bonds of glucose and when glucose is broken down, much of that energy is released.
Cell utilize energy in the form of ATP.
The first step of respiration is called glycolysis. In a series of steps, glycolysis breaks glucose into two smaller molecules - a chemical called pyruvate. A small amount of ATP is formed during this process.
Most healthy cells continue the breakdown in a second process, called the Kreb's cycle. The Kreb's cycle allows cells to “burn” the pyruvates made in glycolysis to get more ATP.
The last step in the breakdown of glucose is called oxidative phosphorylation (Ox-Phos).
It takes place in specialized cell structures called mitochondria. This process produces a large amount of ATP. Importantly, cells need oxygen to complete oxidative phosphorylation.
If a cell completes only glycolysis, only 2 molecules of ATP are made per glucose. However, if the cell completes the entire respiration process (glycolysis - Kreb's - oxidative phosphorylation), about 36 molecules of ATP are created, giving it much more energy to use.
IN CANCER CELL:
Unlike healthy cells that "burn" the entire molecule of sugar to capture a large amount of energy as ATP, cancer cells are wasteful.
Cancer cells only partially break down sugar molecules. They overuse the first step of respiration, glycolysis. They frequently do not complete the second step, oxidative phosphorylation.
This results in only 2 molecules of ATP per each glucose molecule instead of the 36 or so ATPs healthy cells gain. As a result, cancer cells need to use a lot more sugar molecules to get enough energy to survive.
Unlike healthy cells that "burn" the entire molecule of sugar to capture a large amount of energy as ATP, cancer cells are wasteful.
Cancer cells only partially break down sugar molecules. They overuse the first step of respiration, glycolysis. They frequently do not complete the second step, oxidative phosphorylation.
This results in only 2 molecules of ATP per each glucose molecule instead of the 36 or so ATPs healthy cells gain. As a result, cancer cells need to use a lot more sugar molecules to get enough energy to survive.
introduction to WARBERG PHENOMENA:
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.
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 observation that tumor slices consume glucose and secrete lactate at a higher rate than normal tissues.
A reading report for <Tumor microenvironment derived exosomes pleiotropically...星云 王
A reading report for <Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism
>, only for private study use, please do not use it for profit or public.
Carbohydrates are the most abundant biomolecules on the earth. Glycolysis is the first pathway of the cellular respiration used in the breakdown of glucose to extract energy. When energy is needed, metabolic processes mobilize glycogen to produce ATP and give the body fuel. Glycolysis is the major pathway for utilization of glucose & it takes place in the cytoplasm of all the cells of body, as all the glycolytic enzymes required are present in the cytosol. Major pathway for ATP in tissues lacking mitochondria viz. RBC, lens, cornea etc.. Glycolysis is unique because it may be aerobic or anaerobic - meaning it will proceed with or without oxygen also it occurs quickly, and can produce thousands of ATP molecules in milliseconds.
Similar to Cancer metabolism lecture, Hood College (10-18-10) (20)
Postdoc Orientation: Integration Strategies at HMSJames Gould, PhD
At the 11th Annual National Postdoctoral Association (NPA) Meeting (Charleston, 2013) I co-presented with Tom Geoghegan (Louisville) on postdoc orientation strategies at our respective institutions.
I help my advisees to understand that they can frame their training experience, though long and possibly varied, to fit a narrative that they construct. Thus allowing them and potential employers to see their skills in the proper context.
With the changing job landscape scientific training must evolve as well. But what about the current and recent trainees that may not benefit from this enlightened attitude? I argue that we have and are already training a potentially diverse workforce. This coupled with an active postdoc/grad office, provides added value to the institution, lab, and trainee.
it describes the bony anatomy including the femoral head , acetabulum, labrum . also discusses the capsule , ligaments . muscle that act on the hip joint and the range of motion are outlined. factors affecting hip joint stability and weight transmission through the joint are summarized.
A review of the growth of the Israel Genealogy Research Association Database Collection for the last 12 months. Our collection is now passed the 3 million mark and still growing. See which archives have contributed the most. See the different types of records we have, and which years have had records added. You can also see what we have for the future.
Safalta Digital marketing institute in Noida, provide complete applications that encompass a huge range of virtual advertising and marketing additives, which includes search engine optimization, virtual communication advertising, pay-per-click on marketing, content material advertising, internet analytics, and greater. These university courses are designed for students who possess a comprehensive understanding of virtual marketing strategies and attributes.Safalta Digital Marketing Institute in Noida is a first choice for young individuals or students who are looking to start their careers in the field of digital advertising. The institute gives specialized courses designed and certification.
for beginners, providing thorough training in areas such as SEO, digital communication marketing, and PPC training in Noida. After finishing the program, students receive the certifications recognised by top different universitie, setting a strong foundation for a successful career in digital marketing.
A workshop hosted by the South African Journal of Science aimed at postgraduate students and early career researchers with little or no experience in writing and publishing journal articles.
Biological screening of herbal drugs: Introduction and Need for
Phyto-Pharmacological Screening, New Strategies for evaluating
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for Anti-inflammatory, Antiulcer, Anticancer, Wound healing, Antidiabetic, Hepatoprotective, Cardio protective, Diuretics and
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This presentation includes basic of PCOS their pathology and treatment and also Ayurveda correlation of PCOS and Ayurvedic line of treatment mentioned in classics.
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Thinking of getting a dog? Be aware that breeds like Pit Bulls, Rottweilers, and German Shepherds can be loyal and dangerous. Proper training and socialization are crucial to preventing aggressive behaviors. Ensure safety by understanding their needs and always supervising interactions. Stay safe, and enjoy your furry friends!
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Macroeconomics- Movie Location
This will be used as part of your Personal Professional Portfolio once graded.
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Prepare a presentation or a paper using research, basic comparative analysis, data organization and application of economic information. You will make an informed assessment of an economic climate outside of the United States to accomplish an entertainment industry objective.
5. Glucose is the body s major nutrient and energy source
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•
•
•
•
The human body exquisitely maintains
the level of circulating glucose in the
range of 5 mM.
Nearly all carbohydrates ingested in
the diet are converted to glucose
following transport to the liver.
Breakdown of dietary or cellular
proteins generates carbon atoms that
can be utilized for glucose synthesis
via gluconeogenesis.
Additionally, skeletal muscle and
erythrocytes provide lactate that can
be converted to glucose via
gluconeogenesis.
Maintenance of glucose homeostasis
is of paramount importance to the
survival of the human organism.
The same could be said of cancer....
6. Cells alter their metabolism in response to stimuli
•
Microbes and cells from multicellular
organisms have similar metabolic
profiles under similar environmental
conditions.
•
During proliferation, these organisms
both metabolize glucose primarily
through glycolysis, excreting large
amounts of carbon in the form of
ethanol, lactate, or another organic
acid.
•
When starved of nutrients, both rely
primarily on oxidative metabolism.
•
Evolutionarily, there is an advantage
to oxidative metabolism during nutrient
limitation and an advantage in
glycolysis during cell proliferation.
Matthew G. Vander Heiden, et al. Science 324, 1029 (2009)
7. Glycolysis in Normal Tissues
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•
•
•
•
During aerobic glycolysis, pyruvate
in most cells is further metabolized via
the TCA cycle. Aerobic glycolysis
generates substantially more ATP per
mole of glucose oxidized than does
anaerobic glycolysis.
Under anaerobic conditions, pyruvate
is converted to lactate by the enzyme
lactate dehydrogenase (LDH), and
the lactate is transported out of the
cell into the circulation.
The conversion of pyruvate to lactate
provides the cell with a mechanism
for the oxidation of NADH to NAD+
without which glycolysis will cease.
The utility of anaerobic glycolysis, to
a muscle cell when it needs large
amounts of energy, stems from the
fact that the rate of ATP production
from glycolysis is approximately 100X
faster than from OxPhos.
Muscle cells derive almost all of the
ATP consumed during exertion from
anaerobic glycolysis allowing it to
generate the maximum amount of
ATP, for muscle contraction, in the
shortest time frame.
Michael W. King; themedicalbiochemistrypage.org
9. Aerobic Glycolysis: The Warburg Effect
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•
In the presence of O2, nonproliferating tissues
first metabolize glucose to pyruvate via
glycolysis and then completely oxidize most of
that pyruvate in the mitochondria to CO2 during
the process of oxidative phosphorylation
(OxPhos).
Because oxygen is required as the final electron
acceptor to completely oxidize the glucose,
oxygen is essential for this process.
When oxygen is limiting, cells can redirect the
pyruvate generated by glycolysis away from
mitochondrial OxPhos by generating lactate.
Lactate production allows glycolysis to continue
(by cycling NADH back to NAD+), but results in
minimal ATP production when compared with
OxPhos.
Otto Warburg observed that cancer cells tend
to convert most glucose to lactate regardless of
whether oxygen is present (aerobic glycolysis).
This property is shared by normal proliferative
tissues.
Mitochondria remain functional and some
oxidative phosphorylation continues in both
cancer cells and normal proliferating cells.
Aerobic glycolysis is less efficient than OxPhos
for generating ATP. The cells make up for this
by consuming more glucose.
Matthew G. Vander Heiden, et al. Science 324, 1029 (2009)
10. How cancer cells reprogram their metabolism
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Metabolic cross-talk allows for both NADPH
production and Ac-CoA flux for lipid
synthesis.
These metabolic pathways can be
influenced by cell proliferation signaling
pathways.
Activation of growth factor receptors leads to
downstream signaling cascade activation.
PI3K/Akt activation stimulates glucose
uptake and flux through the early part of
glycolysis.
•
•
•
Tyrosine kinase signaling negatively
regulates flux through the late steps of
glycolysis, making glycolytic intermediates
available for macromolecular synthesis as
well as supporting NADPH production.
Myc drives glutamine metabolism, which
also supports NADPH production.
LKB1/AMPK signaling and p53 decrease
metabolic flux through glycolysis in
response to cell stress.
Vander Heiden, et al. Science 324, 1029 (2009)
12. The Warburg effect gives tumor cells a growth advantage
through reduced oxygen consumption
By slowing the consumption
of O2 in the hypoxic cells, O2
diffuses further and fewer
cells reach anoxic levels that
are toxic. Mild hypoxia can
support cellular growth.
Denko, Nature Reviews: Cancer Vol 8; Sept 2008
13. Molecular underpinnings of the Warburg effect
The Warburg effect describes the enhanced conversion of glucose to lactate by tumor cells, even in
the presence of adequate oxygen that would ordinarily be used for OxPhos.
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•
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Activation of the AKT oncogene results in
enhanced glycolytic rates.
MYC oncogene is activates glycolytic
genes and mitochondrial biogenesis,
which can result in reactive oxygen
species (ROS).
ROS could cause mtDNA mutations that
render mitochondria dysfunctional.
p53 stimulates respiration through
activation of a component of the
respiratory chain.
Hypoxic sensor HIF-1 is stabilized and
accumulates
HIF-1 transactivates glycolytic genes as
well as directly activates the PDK1 gene,
which in turn inhibits PDH that catalyzes
the conversion of pyruvate to acetyl-CoA.
Acetyl-CoA enters the TCA cycle, which
donates electrons to the mitochondrial
respiratory chain complexes I to IV.
Inhibition of PDH by PDK1 attenuates
mitochondrial function, resulting in the
shunting of pyruvate to lactate.
Cancer Res 2006; 66: (18). September 15, 2006
15. Global Changes in Cancer Metabolism:
Genetic Mutations
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•
•
•
Mutations and epigenetic changes lead to
changes in the function of oncogenes and
tumor suppressor genes.
Genomic instability causes further changes
that upset the balance of oncogenes and
tumor suppressor genes.
These events lead to changes in the
function of 3 transcription factors: activation
of HIF-1 and MYC and loss of p53 function.
The changes in these transcription factors
cause a coordinated change in the
enzymes, transporters, regulators and
metabolites as well as changes in
mitochondrial function.
This brings about a characteristic metabolic
signature of cancer cells.
This metabolic reprogramming provides
growth and survival advantages for the
cancer cells in the tumor microenvironment.
Cell. Mol. Life Sci. 65 (2008) 3981 – 3999
16. Regulation of Cancer Metabolism:
Protein Signaling Pathways
•
Activation of the AKT signaling may be
sufficient to bring about the switch to
glycolytic metabolism in cancer.
– regulates glucose transporter 1 (GLUT1)
expression
– activates HK2 which promotes
phosphorylation of glucose to glucose 6phosphate
– regulates de novo fatty acid synthesis
and b-oxidation
•
•
Cell. Mol. Life Sci. 65 (2008) 3981 – 3999
mTOR is situated in the crossroads of
signaling pathways and is an integration
center of the signals to bring
coordinated regulation of nutrient
uptake, energy metabolism, cell growth,
proliferation, and cell survival.
mTOR is an upstream activator of
HIF-1a in cancer cells, which is a
subunit of a transcription factor that
upregulates the expression of nearly all
the genes involved in the glycolytic
pathway
17. c-MYC, HIF-1 and p53 Regulates Glycolytic Metabolism:
Transcription
•
The Warburg effect is partly
due to
– increased activity of the
transcription factors MYC
and HIF-1 in cancer cells
– Upregulation of genes
coding for glucose
transporters and glycolytic
and regulatory enzymes
mediated by, and
– A coordinated loss of
regulatory proteins due to
loss of p53 function.
– Loss of p53 function also
leads to activation of
GLUT-3 transcription via
NFkB.
Cell. Mol. Life Sci. 65 (2008) 3981 – 3999
19. HIF has a global effect on metabolism
•
HIF upregulates glycolysis
– Increased uptake of glucose through
glucose transporters GLUT1 and GLUT3.
– Glucose metabolism by the increased
levels of the glycolytic enzymes
– Increased pyruvate levels, which is largely
converted to lactate by LDHA
– Pyruvate is removed from the cell by the
monocarboxylate transporter
•
HIF downregulates OxPhos in
mitochondria
– decreased pyruvate flow into the TCA cycle
– decreased mitochondrial biogenesis
– Switch to high efficiency cytochrome
oxidase
Denko, Nature Reviews: Cancer Vol 8; Sept 2008
20. HIF1α protein structure is important in its regulation
Sites of proline hydroxylation (P402/P564) are indicated in the
O2-dependant degradation domain of the human protein.
Asparagine (N803) hydroxylation in the carboxy-terminal
transactivation domain (TAD) by factor inhibiting HIF (FIH)
regulates HIF1 activity but not stability.
Denko, Nature Reviews: Cancer Vol 8; Sept 2008
21. Mechanisms of (HIF1α) stabilization
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•
•
•
•
Denko, Nature Reviews: Cancer Vol 8; Sept 2008
Oxygen levels are sensed through O2dependent proline hydroxylation on
HIF1α.
This modification is due to one of the
three prolyl hydroxylase (PHD), which
mediate proteasomal degradation.
Oncogenic activation, can also cause
HIF1α stabilization through unknown
mediators.
TCA intermediates such as succinate
and fumarate, or mitochondrial reactive
oxygen species (ROS), can inhibit the
activity of PHDs, also stabilizing HIF1α.
Stabilized HIF1α associates with HIF1β,
which binds to hypoxia-responsive
elements (HREs) in target genes.
Kaelin & Thompson, Nature; Vol 465; 3 June 2010
24. Alternative Nutrients: Amino Acids
All 20 of the amino acids,
excepting leucine and lysine,
can be degraded to TCA cycle
intermediates. This allows the
carbon skeletons of the amino
acids to be eventually
converted to pyruvate. The
pyruvate thus formed can be
utilized by the gluconeogenic
pathway.
25. Vitamin C
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•
•
Vitamin C (L-ascorbic acid, ascorbate, VitC)
is one of the most abundantly produced
substances in plants and living organisms
(but not humans).
VitC is not part of any metabolic pathway in
humans but is an essential co-factor in
many enzymatic reactions.
Studies have suggested that insufficient
dietary intake levels of VitC may adversely
affect health and normal life span in man,
and could be one of the reasons for the
relatively high incidence of cancer in
humans.
Glucose and VitC are six-carbon sugars
whose over-consumption positively and
negatively affects cancer, respectively.
Glucose addiction is a hallmark of cancer
cells, promoting cell proliferation and
increasing the risk of cancer, BUT high
levels of VitC protect multi-cellular
organisms from ROS damage and
uncontrolled cell proliferation.
The Search for the Achilles Heel of Cancer, PeproTech, Inc; 2010
27. Targeting Metabolism for Cancer Therapy
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Small molecule drugs that disrupt
glucose metabolism or decrease
glucose uptake by tumors could
provide anti-cancer therapy
We can visualize altered glucose
metabolism in tumors by 18Fdeoxyglucose positron emission
tomography (FDG-PET)
The ability to inhibit tumor FDG
uptake correlates with tumor
regression
Seen here:
– Malignant sarcoma (gastrointestinal
stromal tumor) before and after
therapy with a tyrosine kinase
inhibitor (sunitinib).
Matthew G. Vander Heiden, et al. Science 324, 1029 (2009)
28. Glycolysis Can Promote Resistance to Cancer Therapy
• Glycolysis provides the metabolites and energy for DNA repair and
chemotherapy drug inactivation/detoxification.
• Glycolysis can provide ATP/NAD+ for DNA repair.
• Glycolysis, pentose phosphate pathway and glutaminolysis can also
provide NADPH
• These mechanisms can potentially contribute to resistance of the
cancer to therapy.
Cell. Mol. Life Sci. 65 (2008) 3981 – 3999
29. Summary
• How cancer changes
metabolism
– Expression of
oncogenes and tumor
suppressors
– Expression/activity of
glycolytic enzymes
– Interactions with
microenvironment
– Aerobic glycolysis
• Why these changes
are advantageous
– Decreased O2
consumption
– Increased Redox
potential
– Faster use of glucose
– Increased building
blocks
– Evasion of cell cycle
checkpoints
31. We study how proline metabolism relates to
the cancer phenotype
Tools:
• O2 Consumption
• Lactate Assay
• Glucose Assay
• ATP Assay
• ROS Assay
• Enzymatic Assays
• Molecular Biology
• Gene silencing
• 2D and 3D culture
• Nutrient Profiling
Phang et al, Annu. Rev. Nutr. 2010. 30:15.1–15.23
32. Cell lines are vital to studying
cancer
• UOK262: Fumarate hydratase deficient (FH-/FH-)
cell line
• HLRCC: hereditary leiomyomatosis renal cell
carcinoma
• Model cell line for the Warburg Effect
– Pseudohypoxic HIF1-α stabilization
– Highly glucose-dependent growth
– Compromised OxPhos and increased anaerobic
glycolysis
– Elevated lactate efflux and GLUT1 expression
33. Activity
• Read questions 1-6, 8-9, 11, 15-16 from
Nature Q&A article Clues from cell
metabolism
• Write a one sentence summary of the
answer…so that a 6th grader could
understand it.
• We will share your answers with the rest of
the class