Summary Molecular Regulation
of Health and Disease
Theme 1
Tumour cell: can be benign, pre-malignant, or malignant. It can also be a lesion without cancerous
potential.
Cancer cell: malignant neoplasm (active and dangerous).
Tumour and cancer cells display cell proliferation and rapid growth. Cancer is considered as a class of
diseases in which a group of cells display uncontrolled growth, but also invasion that intrudes and
destroys adjacent tissues, and sometimes metastasis, spreading to other locations in the body via
lymph or blood. These malignant properties of cancers differentiate them from benign tumours,
which do not invade or metastasize.
Cell transformation: a process of cell change in which a cell loses its ability to control its rate of
division (and becomes a tumour cell).
Cancer cell characteristics:
They are immortal (cancer cell cultures can grow indefinitely)
They display sufficiency in growth signals (lower growth factor requirements)
Cancer cells are invasive: they have loss of contact inhibition, reduced cellular adhesion, have
an altered protein secretion profile, and are less organised
They are resistant to programmed cell death
They have an altered nutrient and energy metabolism: increased rate of glycolysis, and have
more negative surface charge (facilitates nutrient uptake)
Warburg: discovered that cancer cells display a glycolytic metabolism under aerobic conditions. Thus,
lactic acid is produced in tumour cells.
Hallmarks of cancer:
1. Sustaining proliferative signalling
2. Evading growth suppressors
3. Resisting cell death
4. Enabling replicative immortality
5. Inducing angiogenesis
6. Activating invasion and metastasis
7. Evading immune destruction
8. Reprogramming of energy metabolism
Characteristics of mitochondria:
They have a double membrane
They have their own circular DNA
The main function of mitochondria is to produce ATP and to respond to cellular energy requirements.
Reactive oxygen species are produced in mitochondria, which play a role in several oxidative
signalling functions. The function of a mitochondrion is altered in cancer cells.
, Glycolysis: an anaerobic process where 2 molecules of ATP are
made per molecule of glucose. The end-product of glycolysis can be
2 molecules of pyruvate or 2 molecules of lactic acid.
Pyruvate: goes into the TCA cycle and is converted to acetyl-CoA.
Acetyl-CoA is broken down to generate carbon dioxide, NADH, and
FADH2. In the TCA cycle, electrons are provided that can be used in
the respiratory chain or electron transport complexes (ETC). In the
ETC, ATP is produced during a process called the oxidative
phosphorylation. The oxidative phosphorylation requires oxygen.
Anti-oxidant defence: superoxide dismutase converts superoxide to
hydrogen peroxide (both types of ROS). Glutathione peroxidases
can convert hydrogen peroxides further to water. To regenerate these enzymes, NADPH and
glutathione are needed.
High levels of ROS: can cause cell damage (lipid peroxidation and damage to membranes and DNA).
Low levels of ROS: function in cell signalling and maintaining cellular homeostasis.
Apoptosis: occurs through two main interconnected pathways: the intrinsic and the extrinsic
pathway. The extrinsic pathway is a receptor mediated pathway involving death receptors from the
tumour necrosis factor superfamily that are found on the surface of the cell membranes. These
receptors have an extracellular domain to bind the ligands, and activation leads to receptor clustering
and intracellular recruitment of proteins into a death-inducing signalling complex (DISC), which then
activates an initiator caspase.
The intrinsic pathway can be activated by a variety of cellular stresses above a certain threshold.
These cellular stresses include radiation induced damage, free radical induced damage, viral
infections, misfolded proteins, other forms or cell damage or impaired cellular functions and
serum/growth factor withdrawal. Activation of the intrinsic pathway results in mitochondrial
permeabilization to release pro-apoptotic proteins. The proteins can activate the caspase dependent
pathway or the proteins include other cell death proteins such as apoptosis inducing factor and
endonuclease G. Both AIF and Endo G act in a caspase-independent manner to execute cell death,
called programmed necrosis.
To prevent cell death, cells have many specific repair and waste disposal/recycle pathways.
Lysosomes play a central role in waste disposal
and recycling pathways. Around 60 different
types of acid hydrolases are localized in the
lumen of the lysosome to degrade
macromolecules.
Types of degradation:
Ubiquitin mediated proteasomal
degradation: specific, proteins are
degraded. Liberated amino acids can be
used as building blocks for energy
substrates.
Micro-autophagy: small cellular
components are removed by engulfment
by the lysosomal membrane
Macro-autophagy: breaks down organelles and proteins (selective of non-selective)
Endocytosis: components are taken up by the lysosome and degraded
, Macro-autophagy is initiated/activated by two distinct complexes. This occurs by the ATG complex
and the Beclin complex. The ATG complex is the primary initiation complex that is regulated by
nutrient/energy starvation, mainly by mTORC1. PI3KC3 is the functional enzyme that phosphorylates
lipids in the autophagosome by its phopho-inositol 3 kinase (PI3 kinase) activity. The activity of
PI3KC3 is dependent on the two other core components of this complex: BECN1 (also known as
BECLIN1) and PI3KR4. The order of events in mammalian autophagosome biogenesis is:
initiation/activation of double membrane formation by the ATG complex and initiation/activation of
nucleation by Beclin complex. By formation of phosphatidylinositol-3-phosphate (PI3P) a number of
effectors are recruited (Atg12- Atg5-Atg16L and LC3 ) that facilitate membrane elongation. The
double membrane autophagosome maturation is completed by recruitment of Gate-18, that removes
the Atg12-Atg5- Atg16L complex and, together with LC3, takes care of the ultimate maturation of the
double membrane autophagosome.
Growth-factor signalling: regulates the uptake and metabolism of extracellular nutrients in normal
cells. Warburg concluded that mitochondria were damaged since cancer cells produce most of their
ATP via glycolysis. However, further studies showed that mitochondria do respire and produce ATP.
Why the Warburg effect? First, it allows cells to use the most abundant extracellular nutrient,
glucose, to produce abundant ATP. Although the yield of ATP per glucose consumed is low, if the
glycolytic flux is high enough, the percentage of cellular ATP produced from glycolysis can exceed that
produced from oxidative phosphorylation. Second, glucose degradation provides cells with
intermediates needed for biosynthetic pathways. Third, glycolysis requires less cellular volume and
proteins. However, it comes at a cost: more waste is produced (lactate).
Cataplerosis: a continuous efflux of intermediates, when much of the carbon that enters the TCA
cycle is used in biosynthetic pathways that consume rather than produce ATP.
Anaplerosis: a matching influx of intermediates to resupply in case of cataplerosis.
Glutaminolysis: glutamine is partially oxidized to form pyruvate for the TCA cycle, a form of
anaplerosis.
Some types of tumours develop due to a mutation in succinate dehydrogenase (SDH), which converts
succinate into fumarate in the TCA cycle. Loss of SDH leads to accumulation of succinate, which
disturbs oxidative phosphorylation and increases ROS, which can lead to escalation of mutagenesis.
Furthermore, succinate disturbs the regulation of HIF1alpha. HIF1alpha is a transcription factor that
regulates the response to hypoxia and is normally only activated by low levels of oxygen.
Oncometabolite: a metabolite whose abnormal accumulation (succinate or fumarate in the case of a
FH mutation) causes metabolic and non-metabolic dysregulation and potential transformation to
malignancy.
2-HG is also an example of an oncometabolite. 2-HG is an alternative product of the isocitrate
dehydrogenase (IDH) enzyme, that normally converts isocitrate to alpha-ketoglutarate in the TCA-
cycle.
Lipids are a third group of nutrients that are essential for rapid cell proliferation. Lipid synthesis is
highly active for the generation of membrane components during cell proliferation.
Triglycerides can be broken down to support growth of cancer cells. In normal physiology, the adult
heart is the organ that consumes the highest amount of fatty acids for ATP generation. The beta-
oxidation breakdown pathway performs multiple consecutive cycles of 2-carbon atom removal. It
produces acetyl-CoA and generates both FADH and NADH, that can be used for energy generation in
