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PHT801 UNIT 1 & 2 > Unit 2: Cell death and it's deregulation in cancer > Flashcards

Unit 2: Cell death and it's deregulation in cancer Flashcards

1
Q

What are the 2 main forms of cell death?

A

Nectrosis

Apoptosis

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2
Q

What is necrosis

A

Accidental, unregulated and passive cell death (unregulated mass killing) effects groups of cells which release contents resulting in inflamation. (undesirable)

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3
Q

What is a functional consequence of necrosis

A

Loss of tissue function

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4
Q

What is apoptosis

A

Organised, tightly regulated and active process (A.K.A type 1 cell death) - avoids inflamation.
Removed damaged and unwanted excess cells.

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5
Q

Does apoptosis effect an individual cell or a cell mass?

A

Individual cell

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6
Q

What triggers necrosis

A

SEVERE pathological or traumatic event e.g - Severe infection, changes in pH or temp.
Severe metabolic stress
Chemical toxins
Severe lack of nutrients or O2

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7
Q

How to severe events effect the cell and lead to necrosis

A

SEVERE cell injury activates the normal stress response. However, the repair pathways become overwhelmed and ATP becomes severely depleted = lack of active transport leading to ion imbalance = NECROSIS

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8
Q

What are 3 triggers for apoptosis

A

PHYSICAL triggers e.g -
chanhes in GF’s & hormones
Tissue remodelling (hand) & homeostasis during cell growth.
When a cell is no longer needed or maintain balance of cell no.
When there is a need to eliminate DNA damage

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9
Q

What is the other form of cell death and what triggers it

A

Programmed cell death which occures in anchorage dependant cells when they detatch from their surrounding ECM

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10
Q

What are the morphological features of necrosis

A
  • Passive, doesnt need ATP
  • Unregulated
  • intitially its reversable
  • loss of ion homeostasis = loss of active transport
    across PM
  • PM becomes compromised and cell takes up excess
    water and swells
  • organelles swell including LYSOSOMES and nucleus
  • chromatin clumping randomply in nucleus
  • lysosomes release degrading cathepsin enzymes =
    puncture PM further
  • cells lyse and release toxic cellular contents into
    neighbouring cells = inflamation and mass cell death
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11
Q

What are the morphological features of apoptosis

A
  • active, regulated, ATP dependant
  • planned so irriversible after initiation.
  • organised so cells shrink, detatch and round up
  • dense nuclei structure due to chromatin
    condensation
  • regulated by caspases
  • DNA undergoes organised cleavage of 200bp
  • PM blebs but doesnt lyse so contents remains
  • cytoplasms shrinks
  • lysosomes are unafected so no spilling of contents
  • cell remians bound by membrane bound apoptotic
    boddies to prevent release of toxic materials
  • apoptotic bodies trigger phagocytosis via
    phosphotidyl serine residues recognised by
    neighbouring cells
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12
Q

What receptors are on phagocytes which can recognise and bind to the phosphatidy serine residues on apoptotic bodies?

A

Anexin receptors

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13
Q

How long does apoptosis take

A

Around 1 hour

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14
Q

Does apoptosis trigger inflamation and why?

A

No as it doesnt lyse and is cleared promptly. So no inflamatory response which prevents secondary tissue necrosis

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15
Q

What is the intrinsic pathway driven by

A

intracellular signals driven by a non-receptor mediated mechanisms. Involves mitochondrial changes.

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16
Q

List death triggers of the intrinsic pathway

A

Driven by moderate intracellular stress

  • withdrawl of GF’s changes intracellular signalling
  • Metabolic changed e.g ocidative stress
  • mild hypoxia
  • DNA damage
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17
Q

What is the intrinsic pathway driven by

A

Extracellular signals

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18
Q

List death triggers of the extrinsic pathway

A

Mediated by death receptors at PM e.g TNF receptors or FAS receptors.
Ligand binding to these receptors & trigger the pathway.
These ligands are produced by infection and immune response.

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19
Q

What enzymes are involved in apoptosis

A

Initiator and executioner caspases

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20
Q

What is the initiator caspase responsible for triggering the intrinsic pathway

A

Caspase 9

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21
Q

What is the initiator caspase responsible for triggering the extrinsic pathway

A

Caspase 8

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22
Q

Do the intrinsic and extrinsic pathways use different executioner caspases?

A

No, they both use different initiator caspases but the same executioner caspases.

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23
Q

What is autophagy

A

Type 2 programmed cell death. Organised cell death due to nutrient starvation where the cell kills itself

24
Q

What is the process of autophagy

A

Recycles damaged organelles and proteins in order to recover amino acids, sugars and useful proteins.
Forms autophagosoms which wrap around the organelles which then fuse with lysosomes to form autolysosomes. Other cells can then use this nutrients.

25
Q

Which gene regulates autophagy

A

Beclin1

26
Q

When does autophagic cell death occur

A

When there is a SEVERE nutrients loss which kills cells via a caspase indipendant mechansism

27
Q

What enzymes are linked to autophagy

A

Calpanes - Damage mitochondria

28
Q

What associated enzymed are linked to Necrosis, apoptosis and autophagy

A

Necrosis - cathepsins
Apoptosis - Caspases
Autophagy - Calpanes

29
Q

Outline the 3 keys stages of the intrinsic pathway of apoptosis

A
  1. Initiation
  2. Effector phase
  3. Degredation phase
30
Q

What are the main domains of the BCL family

A

BCL-2 homology domains (BH domains). Each BCL family member can have up to 4 of these.

31
Q

What do BCL-2 homology domains facilitate

A

Conntain BH3 which faciliatate protein-protein interaction

32
Q

What does the BCL-2 family of proteins regulate

A

regulate the permeability of the mitochondria

33
Q

HOW does the BCL-2 family of proteins regulate mitochondrial permeability

A

The family contains pro and anti-apoptotic proteins which need to be BALANCED in order to regulate channels within the mitochondrial membrane

34
Q

What are the pro-survival proteins in the BCL family

A

BCL-2 - found on outer mitochondrial membrane and keeps channels CLOSED
All contain all 4 BH domains

35
Q

What are the pro-apoptotic proteins in the BCL family

A

BH3 only domains - BAD, BID, BIM (recognise stress)

Multiple BH domains - BAX, BAK (Effectors)

36
Q

Outline the initiation phase of the intrinsic apoptotic pathway

A
  • Death signals are transmitted intracellularly
  • increases pro apoptotic BH3 domain proteins
    (sensors), BAD, BID
  • This outweighs pro-survival members: BCL-2
  • These bind to BCL-2 via thier BH3 domain and
    neutralise them.
  • Allows pro-apoptotic effectors BAK, BAX to be
    displaced and form complexes with eachother which i nsert onto the outer mitochondrial membrane.
37
Q

Outline the Effector phase of the intrinsic apoptotic pathway

A
  • BAK/BAX complextes open channels in
    mitochondrial membrane causinng permealisation.
  • This compromises walls of mitochondria which
    releases death proteins out into the cytosol
    (cytochrome C, pro-caspase9).
  • These interact with APAF-1 which forms an
    apoptosome which cleaves pro-caspase .
  • Pro-caspase 9 transmits the apoptotic signal by
    cleaving pro-caspase 3, 6 and 7.
  • These cleave the death substrates in the
    degredation phase…
38
Q

What does MOMP stand for

A

Mitochondrial outer membrane permealisation caused by pro-apoptotic BAK/BAX complex opening channels on the outer membrane.

39
Q

What are the two death proteins released from the mitochondria during the intrinsic apoptotic pathway

A

Cytochrome C

Pro-caspase9

40
Q

Name the executioner caspases

A

Caspase 3,6 and 7

41
Q

At what residues does cleavage of pro-caspases occur at?

A

Aspartate residues

42
Q

Outline the degredation phase of the intrinsic apoptotic pathway

A
  • Death substartes are celaved by executioner
    caspases (caspase-3), e.g-
  • DNAse inhibitor = allows nuclear DNA to be
    fragmented.
  • Break down of lamin = breaks down the nucleus
  • cytosolic proteins = causes blebbing & formation of
    apoptotic bodies.
43
Q

Outline the extrinsic apoptotic pathway

A
  • initiated at PM
  • TNF receptor or FAS bind death ligand & trimerise
  • This exposes the death domain of the receptors
  • this recruits DISC = death inducing signalling
    complex (FADD) this binds to the death receptor
  • DISC complex also recruits precursor of procaspase
    8 (initiator caspase) and cleaves it
  • This cleaves the executioner caspases (3,6,7)
  • activates their aspartic residues
  • triggers death substrates and causes apoptosis
44
Q

What does DISC stand for

A

Death inducing signalling complex

45
Q

Name a cancer hallmark related to cell death

A

Ability to evade programmed cell death (intrinsic/extrinsic apoptosis)

46
Q

What main apoptotic proteins are alteres in cancer to enable survival

A
  • Over expression of pro-survival protein BCL-2
  • inactivation of pro-apoptotic protein BAD via
    hyperactive AKT signalling
47
Q

How does abberant AKT signalling increase survival

A

AKT pathway phosphorylates pro-apoptotic protein BAD which prevents it from binding and inactivatinng BCL-2.

48
Q

Name some consequences of cells which evade apoptosis in cancer

A

-Prolonged survival so theyre able to aquire even more mutations

49
Q

How can autophagy be utilised by tumours for suvival

A

Growing tumours can use deregulated autophagy to maintain viabilty when nutrients level falls during tumour progression.

50
Q

Which gene is considered the ‘‘guardian of the genome’’ and what funtion does it have

A

p53 gene
Nuclear TF which accumulates in the nucleus after DNA damage or stress. This causes cell cycle arrest and allowing time for DNA repair.

If DNA damage is severe, p53 can act as an emergency control button to trigger apoptosis via nuclear transcription of pro-apoptotic genes and surpression of anti-apoptotic genes.

51
Q

How is p53 deregulated in cancer

A

p53 mutations mean it cant regulate and check DNA damage. It has severe deregulation of its pro-apoptotic funtion allowing cancer cells to survive.

52
Q

What is a hallmark of p53 mutation

A

Increased nuclear signals of p53 in cancer

53
Q

What other mutations can disrupt p53 funtion

A
  • p53 loss
  • mis-localisation of p53
  • changes in p53 regulators
  • ocasional inherited mutation of p53
  • inactivation of p53 via tumour viruses
54
Q

What is lee frau many syndrome

A

multiple simultanious cancers at young age due to inherited p53 mutation which increases the susceptiilty to cancer.

55
Q

How does chemo work

A

Damages DNA to trigger natural apoptotic response - means you need a fully functioning apoptosis response for chemo to work.

PHT801 UNIT 1 & 2 (4 decks)

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