Cancer Metabolism (54)

Question 1

How is Cancer Cell Metabolism different?

Answer 1

Normal Tissue: no lactate production

Tumor tissue: lactate production

Question 2

The Warburg Theory of Cancer

Answer 2

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

Question 3

The Warburg Effect

Answer 3

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.

Question 4

Higher glucose uptake correlates with

Answer 4

more aggressive phenotypes and poorer clinical outcomes

Question 5

Clinical FDG-PET Scanning exploits cancer metabolism

Answer 5

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

Question 6

Hyperacidity of Tumors

Answer 6

Metabolic products of glycolysis leads to spatially heterogenous but consistent acidification of cancer cell environment

Question 7

How Warburg is Advantageous

Answer 7

1. The warburg effect gives tumor cells a growth advantage through reduced oxygen consumption
2. Altered Metabolism provides substrates for biosynthetic pathways

Question 8

1. The warburg effect gives tumor cells a growth advantage through reduced oxygen consumption

Answer 8

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

Question 9

2. Altered Metabolism provides substrates for biosynthetic pathways

Answer 9

• 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

Question 10

Warburg Hypothesis

Answer 10

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.

Question 11

Iron-containing protein complexes

Answer 11

Role: These complexes play a crucial role in the oxidation process.

Question 12

Nicotinamide Cofactor

Answer 12

Nicotinamide serves as a cofactor in cellular processes, influencing oxidation and other essential functions.

Question 13

Spectrometry with Light

Answer 13

A technique developed for substance analysis, particularly using light for spectrometry.

Question 14

Compare the metabolic characteristics of cancer cells and normal proliferative tissues based on the Warburg Hypothesis.

Answer 14

Highlight the significance of aerobic glycolysis, the role of iron-containing protein complexes, and the influence of nicotinamide cofactor in cellular processes.

Question 15

Altered Metabolism in Cancer Cells

Answer 15

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.

Question 16

Microenvironmental acidosis

Answer 16

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.

Question 17

Cause: Mutations and epigenetic changes in oncogenes and tumor suppressor genes.

Answer 17

Consequence: Genomic instability upsets the balance of these genes, leading to altered functions.

Question 18

Changes: Altered transcription factors - activation of HIF-1 and MYC, loss of p53 function.

Answer 18

Effect: Increased activity of MYC and HIF-1 leads to upregulation of genes for glucose transporters and glycolytic enzymes.

Question 19

Loss of p53 function leads to

Answer 19

a coordinated loss of regulatory proteins and activation of GLUT-3 transcription via NFκB.

Question 20

Metabolic signature

Answer 20

Changes in transcription factors cause a coordinated change in enzymes, transporters, regulators, and metabolites, forming the characteristic metabolic signature of cancer cells.

Question 21

Mutations and epigenetic changes alter regulatory pathways.

Answer 21

AKT signaling activation triggers the shift to glycolytic metabolism in cancer cells.

Question 22

mTOR Activation

Answer 22

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.

Question 23

Objective: Understand the role of mitochondria in the Warburg effect.

Answer 23

Key Feature: Decrease in oxidative phosphorylation (OXPHOS) is associated with the Warburg effect.

Question 24

HIF-1 and Pyruvate Dehydrogenase Complex

Answer 24

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

Question 25

Respiratory Activity Depression

Answer 25

Observation: Depression of respiratory activity in cancer cells.

Consequence: Mitochondrial dysfunction contributes to the Warburg effect.

Question 26

mtDNA Mutation and Reactive Oxygen Species (ROS)

Answer 26

Cause: mtDNA mutation in cancer cells.

Effect: Increased generation of Reactive Oxygen Species (ROS), destabilizing supercomplex and enhancing glycolysis.

Question 27

Glycolysis in cancer cells.

Answer 27

Resistance: Glycolysis promotes resistance to cancer therapy.

Question 28

Glycolysis for ATP/NAD+ in DNA Repair

Answer 28

Function: Glycolysis provides ATP/NAD+ for DNA repair processes in cancer cells.

Question 29

Glycolysis for DNA Repair and Drug Detoxification

Answer 29

Role: Glycolysis provides metabolites and energy for DNA repair.

Detoxification: Glycolysis helps inactivation/detoxification of chemotherapy drugs.

Question 30

NADPH Production Pathways

Answer 30

Pathways: Glycolysis, pentose phosphate pathway, and glutaminolysis.

Purpose: These pathways contribute to NADPH production in cancer cells.

Question 31

Contribution to Therapy Resistance

Answer 31

Connection: Mechanisms providing metabolites, energy, and NADPH in cancer cells.

Impact: These mechanisms can potentially contribute to the resistance of cancer to therapy.

Question 32

ATP production compensation

Answer 32

Challenge: Glycolysis has lower ATP production efficiency than oxidative phosphorylation.

Response: Cancer cells upregulate glucose transporters to increase glucose import into the cytoplasm.

Question 33

Growth Advantage

Answer 33

Advantage: The Warburg effect provides tumor cells with a growth advantage.

Mechanism: Reduces oxygen consumption and provides substrates for biosynthetic pathways.

Question 34

Hypoxic microenvironment

Answer 34

Selection: Hypoxic microenvironment selects for altered metabolism in cancer cells.

Question 35

mtDNA Mutation effects

Answer 35

Consequence: mtDNA mutation in cancer cells.

Effects: Increased ROS generation, destabilization of supercomplexes, reduced respiration, and enhanced glycolysis.

Question 36

Altered Metabolism

Answer 36

Result: Altered metabolism in cancer cells.

Causes: Altered transcription of metabolic enzymes and signaling pathways.