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Samenvatting - BMS37 Cell Death in Life and Disease (MED-BMS37)
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Cell deathSSA – Cell adaptation, injury and death – 30/10
Inhibiting Apoptosis
Some heat shock proteins (HSPs) play a key role in maintaining cell survival, above and beyond
preventing accumulation of toxic protein aggregates, etc., as outlined above. HSPs bind and block
several proteins that trigger programmed cell death (PCD) (which is discussed below). HSP pro-
survival actions include the following:
• inhibiting mitochondrial release of cytochrome c and SMAC/Diablo
• preventing Bax from entering mitochondria
• inhibiting apoptosis protease activating factor (Apaf-1)
• blocking procaspases-3 and -9 from conversion to their active, apoptosis-triggering forms,
caspases-3 and 9
• preventing signaling via certain cell death–related receptors (FasR, TNFα)
In addition to unplanned murder of cells by external violence, which is called necrosis, there are
diverse suicide programs: apoptosis, autophagic cell death, necroptosis, NETosis, and so forth. To
further complicate matters, many of these pathways interconnect, so that clear-cut distinctions are
not always possible.
Coagulative necrosis: specific light microscopic appearances of dead or dying cells
• Pyknosis: The nucleus becomes smaller and stains deeply basophilic as chromatin clumping
continues.
• Karyorrhexis: The pyknotic nucleus breaks up into many smaller fragments scattered about
the cytoplasm.
• Karyolysis: The pyknotic nucleus may be extruded from the cell or it may progressively lose
chromatin staining.
Apoptosis is a pattern of cell death that is triggered by a variety of extracellular and intracellular
stimuli and is carried to its conclusion by organized cellular signaling cascades.
Necrosis
1. Interruption of blood supply decreases delivery of O2 and energy nutrients (glucose and
fatty acids)
2. Anaerobic glycolysis leads to overproduction of lactate and decreased intracellular pH
3. Distortion of the activities of pumps in the plasma membrane skews the cell's ionic balance
4. Activation of phospholipase A2 (PLA2) and proteases disrupts plasma membrane and
cytoskeleton
5. Calcium activates proteases that attack the cytoskeleton and its attachments to the cell
membrane
6. Lack of O2 impairs mitochondrial electron transport, decreasing ATP and increasing ROS
7. Mitochondrial damage promotes cytochrome c release in the cytosol
8. The cell dies
Classifications of programmed cell death
• Apoptosis is a highly conserved cell death program that depends on a family of cysteine
proteases (caspases) as crucial signaling intermediates and executioners. Among the various
forms of PCD, it is the most studied and best understood (see below).
, • Necroptosis is a type of cell death in which cells can execute necrosis in a programmed
fashion. It occurs, for example, in the setting of viral infection in which cells undergo
“suicide” via caspase-independent pathways in the presence of viral caspase inhibitors.
Necroptosis also occurs in noninfectious inflammatory settings such as Crohn disease,
myocardial infarction, and pancreatitis.
• Pyroptosis is related to necroptosis. It occurs in response to infection with intracellular
pathogens such as bacteria or viruses. Recognizing the presence of intracellular “foreign
danger signals,” immune cells respond by producing proinflammatory cytokines which, along
with other mechanisms, cause the infected cells to swell and burst. Unlike apoptosis,
pyroptotic cell death involves plasma membrane rupture, releasing damage-associated
molecular pattern (DAMP) molecules into the extracellular space. DAMPs recruit additional
immune cells to help clear the infection. For example, macrophages infected with
Salmonella undergo pyroptosis caused by recognition of the bacteria protein flagellin.
• Anoikis is a form of PCD in anchorage-dependent cells that become detached from the ECM.
Metastatic tumor cells are especially adept at evading this type of cell death
• Entosis is another response to loss of attachment to the ECM, in which a living detached cell
invades the cytoplasm of another cell. First described in cancer, entotic tumor cells may
grow within invaded cells and cannibalize their nutrients.
• NETosis is a form of PCD that involves neutrophil extracellular traps (NETs), extracellular
fibrous networks composed mainly of DNA and proteins released by neutrophils which bind
pathogens and aid in their elimination. As a first line of defense against invading pathogens,
NETosis by neutrophils not only immobilizes pathogens, but also aids incoming neutrophils
in killing pathogens while minimizing damage to host cells. NETosis also facilitates tumor
growth and spread
Apoptosis relies on caspase cascades
• Intrinsic pathway: suicide program activated in a cell that is undergoing stress
• Extrinsic pathway: cell kills itself in response to signals sent by other cells
LE – Introduction to the course – 31/10
Cell stress: alterations in the internal and external cell environment
• Leads to dysfunction on organ and system level. This is where disease occurs
Examples of internal and external stress
• Mechanical stress
• Infection
• Hyper/hypothermia
• Toxins
• Energy shortage (hypoxia, mitochondrial disorders, starvation)
• Living and ageing
Reactions to stress on the tissue/cell level
• When adaptation is possible → cell survival
o Atrophy: reduction in size and function of a cell → saves energy
o Hypertrophy: increase in cell size and function → e.g. in the heart it affects pumping
or blocks entry
o Hyperplasia: increase in cell number → can lead to cancer
o Metaplasia: change in differentiation state → one step to a malignant stage
, o Dysplasia: disorganized tissue structure → probably will lead to cancer if not
monitored
• Cellular senescence: cells are in a “zombie state”. They are alive but do not function in a
normal way → in a between state
o Cells do more harm than good
• When adaptation is impossible → cell death
o Apoptosis
o Necrosis
o Necroptosis
o Autophagy
o Pyroptosis
→ these processes can lead to more or less inflammation which is a key process
Cell phases
• Labile cells: continuously in cell cycle by absence of damage until a signal says they should go
out
o When damage occurs: cells go into apoptosis
• Stable cells: effective in G0, not interested in replication.
o If the need arises, they can still enter the cell cycle
o Quiescent cells
• Permanent cells: terminally differentiated
o Limited potential for regrowth
o If lost, they are lost forever
Cellular senescence
• Hallmarks
o Irreversible cell cycle arrest
o Apoptosis resistance: benefit of keeping cells alive. They can signal to environment
for wound healing
o These signals are: Senescence-associated secretory phenotype (SASP) production
• Can be caused by
o Oxidative stress
o DNA damage
o Replicative stress (telomere shortening/ dysfunction)
o Oncogene activation/ defective apoptotic signaling
• Senescence works as a tumor suppressor mechanism because cells cannot
proliferate anymore
• Accumulates strongly with age
o Increased rate of damage and impaired immune-mediated removal play an
important role in this
o The older, the more persistent damage
Cell cycle in cancer: cancer is a process of uncontrolled cell proliferation
1. Cell cycle disturbed: p53/ RB system
2. Regulation of apoptosis disturbed: Bcl system, role of mitochondria
3. Metabolism disturbed: VHL, IDH
→ in cancer, there is more proliferation than apoptosis, while this is normally equally divided
Cell cycle visualization
• Cdt1 is expressed in G1 but degraded by geminin from S-phase on
, o Cdt1: licensing factors, makes sure that MCM binds to
specific part in DNA because you cannot have multiple
copies in the cell cycle
o Geminin: DNA replication licensing inhibitor, is active from
S phase onwards
o MCM: DNA helicase → crucial for DNA replication and
elongation.
• Labeling proteins → gives the opportunity to see in which phase of
the cell cycle you are
o When you block the cell cycle in the G1 it gets stuck here.
This will cause stress and leads to apoptosis
o In the S-phase Cdt1 is degraded by geminin
Epigenetic modification: HDAC (histone deacetylation) inhibitors
• HDAC decides which genes are on by taking off acetyl group from
histones which makes them less accessible for transcription
• VPA can cause growth arrest and induce differentiation of transformed cells in culture
through HDAC inhibition
o Apoptosis induction through upregulation of pro-apoptotic proteins
Reactive oxygen species (ROS)
• All kinds of stress can lead to ROS
o Oxygen deprivation
o Physical trauma
o Inflammation
o Infectious agents
o Genetic defects
• Electron transport in mitochondria: O2 → H2O
o O2 accepts 4 electrons to form 2H2O
o Enzymes detoxify radicals: SOD and CAT
o No enzymes to detoxify → hydroxyl radical → cellular damage
Hemochromatosis: iron storage disease due to Hfe mutation → too many iron uptake
• Fenton reaction leads to detoxification iron (Fe2+ → Fe3+), iron reacts with hydrogen
peroxide (H2O2) which creates hydroxyl radicals (HO-) and cannot be detoxified → cell
damage
• Effects of hydroxyl radicals
o Lipid peroxidation: induces dysfunction with propagation as a key step
o Protein oxidation: disruption of protein structures
o DNA damage: attacks on purine lead to mutations if the cell tries to copy or repair its
DNA
• Results in
o Chronic damage membranes, proteins and DNA in cell with Fe(II) → liver has biggest
impact
o Membrane disintegration → cell death
o Further damage by ROS release
o Continuous balance in cell disruption and regeneration
• Is damaging to all organs that use iron: liver, pancreas, heart and skin
• Patients with hemochromatosis have a 20-200 fold increased chance of developing hepatic
cancer. Mostly because DNA damage occurs
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