Cancer Metabolism (54) Flashcards
How is Cancer Cell Metabolism different?
Normal Tissue: no lactate production
Tumor tissue: lactate production
The Warburg Theory of Cancer
Cancer, above all other diseases, has countless secondary causes. But, even for cancer, there is only one primary cause. Summarized in a few words, the prime cause of cancer is the replacement of the respiration of oxygen in normal body cells by a fermentation of sugar
The Warburg Effect
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
Observation: Otto Warburg noted cancer cells convert most glucose to lactate regardless of oxygen presence.
Phenomenon: Known as aerobic glycolysis.
Higher glucose uptake correlates with
more aggressive phenotypes and poorer clinical outcomes
Clinical FDG-PET Scanning exploits cancer metabolism
cancer cells must compensate for the `18 fold lower efficiency of ATP production afforded by glycolysis relative to mitochondrial oxidative phosphorylation
cancer cells upregulate glucose transporters, which substantially increases glucose import into the cytoplasm
Hyperacidity of Tumors
Metabolic products of glycolysis leads to spatially heterogenous but consistent acidification of cancer cell environment
How Warburg is Advantageous
- The warburg effect gives tumor cells a growth advantage through reduced oxygen consumption
- Altered Metabolism provides substrates for biosynthetic pathways
- 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 farther and fewer cells reach levels that are toxic.
Mild hypoxia can support cellular growth
- Altered Metabolism provides substrates for biosynthetic pathways
- Aerobic glycolysis is about 100 times faster than oxidative phosphorylation in mitochondria
- increased glycolysis allows the diversion of glycolytic intermediates
- Facilitates the biosynthesis of the macromoleucles and organelles required for assembling new cells
- Ensures that cancer cells have ready supply of hte building blocks needed for macromolecule synthesis
Warburg Hypothesis
Otto Warburg’s observation that cancer cells exhibit aerobic glycolysis, converting most glucose to lactate regardless of oxygen availability. This property is also shared by normal proliferative tissues.
Iron-containing protein complexes
Role: These complexes play a crucial role in the oxidation process.
Nicotinamide Cofactor
Nicotinamide serves as a cofactor in cellular processes, influencing oxidation and other essential functions.
Spectrometry with Light
A technique developed for substance analysis, particularly using light for spectrometry.
Compare the metabolic characteristics of cancer cells and normal proliferative tissues based on the Warburg Hypothesis.
Highlight the significance of aerobic glycolysis, the role of iron-containing protein complexes, and the influence of nicotinamide cofactor in cellular processes.
Altered Metabolism in Cancer Cells
Cause: The altered metabolism in cancer cells is driven by the tumor microenvironment, specifically adapting to hypoxic conditions.
Adaptation: Persistent metabolism of glucose to lactate in aerobic conditions is an adaptation to intermittent hypoxia in premalignant lesions.
Microenvironmental acidosis
Consequence: Upregulation of glycolysis in cancer cells leads to microenvironmental acidosis.
Advantage: Cells with upregulated glycolysis and acid resistance gain a growth advantage, promoting unconstrained proliferation and invasion.
Cause: Mutations and epigenetic changes in oncogenes and tumor suppressor genes.
Consequence: Genomic instability upsets the balance of these genes, leading to altered functions.
Changes: Altered transcription factors - activation of HIF-1 and MYC, loss of p53 function.
Effect: Increased activity of MYC and HIF-1 leads to upregulation of genes for glucose transporters and glycolytic enzymes.
Loss of p53 function leads to
a coordinated loss of regulatory proteins and activation of GLUT-3 transcription via NFκB.
Metabolic signature
Changes in transcription factors cause a coordinated change in enzymes, transporters, regulators, and metabolites, forming the characteristic metabolic signature of cancer cells.
Mutations and epigenetic changes alter regulatory pathways.
AKT signaling activation triggers the shift to glycolytic metabolism in cancer cells.
mTOR Activation
Key Target: AKT targets mTOR, activating lipid and nucleic acid biosynthesis, as well as angiogenesis pathways.
Role: mTOR is an upstream activator of HIF-1α, a transcription factor upregulating glycolytic pathway genes in cancer cells.
Objective: Understand the role of mitochondria in the Warburg effect.
Key Feature: Decrease in oxidative phosphorylation (OXPHOS) is associated with the Warburg effect.
HIF-1 and Pyruvate Dehydrogenase Complex
Connection: Increased HIF-1 activity in cancer cells.
Effect: Reduced expression and activity of pyruvate dehydrogenase complex, leading to decreased carbon input into the Krebs cycle
Respiratory Activity Depression
Observation: Depression of respiratory activity in cancer cells.
Consequence: Mitochondrial dysfunction contributes to the Warburg effect.
mtDNA Mutation and Reactive Oxygen Species (ROS)
Cause: mtDNA mutation in cancer cells.
Effect: Increased generation of Reactive Oxygen Species (ROS), destabilizing supercomplex and enhancing glycolysis.
Glycolysis in cancer cells.
Resistance: Glycolysis promotes resistance to cancer therapy.
Glycolysis for ATP/NAD+ in DNA Repair
Function: Glycolysis provides ATP/NAD+ for DNA repair processes in cancer cells.
Glycolysis for DNA Repair and Drug Detoxification
Role: Glycolysis provides metabolites and energy for DNA repair.
Detoxification: Glycolysis helps inactivation/detoxification of chemotherapy drugs.
NADPH Production Pathways
Pathways: Glycolysis, pentose phosphate pathway, and glutaminolysis.
Purpose: These pathways contribute to NADPH production in cancer cells.
Contribution to Therapy Resistance
Connection: Mechanisms providing metabolites, energy, and NADPH in cancer cells.
Impact: These mechanisms can potentially contribute to the resistance of cancer to therapy.
ATP production compensation
Challenge: Glycolysis has lower ATP production efficiency than oxidative phosphorylation.
Response: Cancer cells upregulate glucose transporters to increase glucose import into the cytoplasm.
Growth Advantage
Advantage: The Warburg effect provides tumor cells with a growth advantage.
Mechanism: Reduces oxygen consumption and provides substrates for biosynthetic pathways.
Hypoxic microenvironment
Selection: Hypoxic microenvironment selects for altered metabolism in cancer cells.
mtDNA Mutation effects
Consequence: mtDNA mutation in cancer cells.
Effects: Increased ROS generation, destabilization of supercomplexes, reduced respiration, and enhanced glycolysis.
Altered Metabolism
Result: Altered metabolism in cancer cells.
Causes: Altered transcription of metabolic enzymes and signaling pathways.
