Molecular regulation of Health and Disease

Theme 1 - Molecular regulation of energy and
nutrient metabolism
Introlecture
OLD hallmarks of cancer
1. Sustaining proliferative signaling
a. Abnormal receptors (always activated)
b. Produce their own activation signals
c. Activation of downstream signaling
pathways
2. Resisting cell death
a. Cell death programs are altered
→ survive even when damaged
3. Evading anti-growth
a. tumor suppressors block cell proliferation when cells are damaged (p53, Rb),
mutated in cancers
4. Replication potential
a. altered telomeres → continued replication → immortal cells in culture
5. Angiogenesis = formation of blood vessels
a. lack of nutrients drives angiogenesis
b. activating blood vessel formation (VEGF)
c. immune cell infiltration promote angiogenesis
6. Activating invasion and metastasis
a. epithelial to mesenchymal transition, spread to distant sites

NEW hallmarks of cancer
Signaling and Metabolism are integrated

Survival of cancer cells
Metabolic reprogramming to maximize
- Alternative fuels
- Antioxidant defense

,Cancer cell metabolism and function


glutamate can be converted to lipids via
2 ways.

PPP = pentose phosphate pathway
→ ribose nucleotides
→ building blocks for DNA
→ NADPH is also formed




Apoptosis
Intrinsic Extrinsic

activated by a variety of cellular stresses receptor mediated pathway involving death
above a certain threshold receptors from the tumor necrosis factor
- radiation induced damage superfamily that are found on the surface of
- free radical induced damage the cell membranes
- viral infections These receptors have an extracellular
- misfolded protein domain to bind the ligands, and activation
- other forms of cell damage leads to receptor clustering and intracellular
- impaired cellular functions and recruitment of proteins into a death-inducing
serum/growth factor withdrawal signaling complex (DISC)
Activation of the intrinsic pathway results in
mitochondrial permeabilization to release
pro-apoptotic factors
→ Caspase cascade
OR
→ caspase independent
apoptosis inducing factor (AIF) and
endonuclease G (endo G)
programmed necrosis.

,Glucose and glutamine use in cancer and normal cells
The Warburg effect
- rate of glucose uptake increases
- lactate is produced
- even in the presence of oxygen and fully
functioning mitochondria

Tumor cells are more similar to cells of growing
embryo
- Take up 100x more glucose
- Uses glucose for making building block
rather than energy
- Can function when access to oxygen is low
- Formation of vast amounts of lactate
affects the microenvironment

Pasteur effect = high oxygen inhibits anaerobic glycolysis in yeast

The benefits
➢ Rapid ATP synthesis
○ lactate production → 2 ATP
○ aerobic respiration → 30 ATP
○ but lactate production is much faster, more ATP production per time unit


➢ Biosynthesis
○ promotes cell growth
○ ribose used for DNA
○ NADH used for antioxidant defense
and lipid biosynthesis
➢ Tumor microenvironment
○ production of lactate
○ acidic environment
○ makes it easier to take up glucose
○ less glucose for immune cells
○ enhances disruption of tissue
architecture and immune cell evasion
➢ Cell signaling
○ higher glucose turnover than in
normal cells
○ more pyruvate converted to acetyl-CoA (=signaling molecule) by ROS
○ more acetylated histones
○ less dense DNA

, Glutamine
glutaminolysis = glutamine → pyruvate, in mitochondria
glutamine plays a role in:
- NAD/NADH (during lactate production)
- lipid synthesis (reductive carboxylation = reversed TCA cycle)
→ mainly used during hypoxia
- purines/pyrimidines = nucleotides used for DNA synthesis




metabolic labeling studies = isotopic C atom is
used as label to follow where a certain
molecule ends up