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Cancer Biology > CBIO3.2: Apoptosis > Flashcards

CBIO3.2: Apoptosis Flashcards

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1
Q

What is apoptosis? When does it occur?

A

Programmed cell death where the cell is responding to defects that cannot be repaired, like extensive DNA damage. This response prevents the damaged cell from dividing and replicating the error. External signals can also trigger apoptosis.

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2
Q

What is apoptosis triggered by?

A

The activation of a cascade of proteolytic enzymes, the caspases.

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3
Q

How does apoptosis occur (v brief)

A

Cell is progressively broken down and consumed by other cells.

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4
Q

What is one of the most important apoptosis-triggering proteins?

A

The p53 tumour suppressor

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5
Q

What does p53 do?

A

Identifies irreparable DNA damage and signals to the cell to undergo apoptosis.

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6
Q

Upon activation of apoptosis cells undergo major changes, what are they?

A 
Cell shrinkage
Nuclear condensation and fragmentation
Surface expression of membrane phospholipid - phosphatidylserine
Membrane blebbing
Mitochondrial depolarisation 
DNA fragmentation
Formation of apoptotic bodies
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7
Q

What are the two pathways by which activation can occur?

A

Extrinsic

Intrinsic

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8
Q

Why is the extrinsic pathway called such?

A

Initiated from outside the cell

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9
Q

What is the extrinsic death pathway initiated by?

A

Other cells, commonly by subsets of T-lymphocytes. These lymphocytes have a surface molecule called FAS Ligand. The EDP is initiated whenever FAS L binds to the FAS receptors on the surface of the targeted cell. This sets off a chain of intracellular events that will eventually lead to apoptosis.

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10
Q

What is the sequence of chain of intracellular events mediated by?

A

FAS associated death domain (FADD)

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11
Q

What is the final step of the extrinsic death pathway?

A

Caspases activate eachother, called the caspase cascade. Apoptosis is then initiated as the caspases breakdown the cellular material

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12
Q

Why is the intrinsic pathway called such?

A

It is initiated from inside the cell

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13
Q

What is the intrinsic pathway regulated by?

A

Maintaining a balance of anti (Blc2/Blcx) and pro-apoptotic proteins (BAX/BAK/BAD/BID)

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14
Q

In a health cell what happens between pro and anti-apoptotic cells?

A

They bind to each other, there by blocking their action

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15
Q

How does the intrinsic death pathway occur?

A

Blc2/Blcx are blocking from binding to BAX/BAK. BAX/BAK are then able to punch holes into the mitochondria, allowing mitochondrial substances suchas cytochrome-C to leak out into cytoplasm. The leaked cyct-c binds to APAF-1 proteins to create a compound that then activates the caspase cascade

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16
Q

What does apoptosis play an important role in? (3)

A

Growth
Immune surveillance
neoplastic development

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17
Q

Name the plasma death receptors and their ligands

A
  • Fas cell surface death receptor (FAS): CD95 (FasL)
  • Tumour necrosis factor (TNF) 1A receptor (TNFR1): TNF
  • TNFRSF10a (TRAILR1, DR4): Apo2L
  • TNFRSF10b (TRAILR2, DR5): Apo2L
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18
Q

What does surface receptor interaction with the death ligand lead to?

A

An assembly of a dynamic multiprotein complexes at the intracellular tail of the receptor, death-inducing signalling complex (DISC).

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19
Q

What is the cytoplasmic domain of the death receptors called?

A

“death domain” (DD)

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20
Q

During TNF ligand and TNFR binding a what is recruited together with FADD?

A

TNFR1-associated death domain protein (TRADD)

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21
Q

Following TRADD and FADD binding, what happens in the intrinsic death pathway?

A

Adaptor proteins exhibit appropriate death domains to bind to their corresponding receptor, and they then recruit procaspase-8 via dimerization of another domain, the the death effector domain (DED). Now, DISC is formed and caspase-8 is cleaved and activated. Active caspase-8 initiates apoptosis by cleaving and activating executioner caspase-3.

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22
Q

What is efferocytosis?

A

A process of clearance by macrophages and other phagocytic cells

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23
Q

Why do the apoptotic cells retain their plasma membrane integrity and metabolic activity during the apoptotic process?

A

Efferocytosis

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24
Q

What is secondary necrosis?

A

Apoptotic cells have a complete breakdown of the plasma membrane and acquire necrotic morphology

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25
Q

What does MOMP stand for?

A

mitochondrial outer membrane permeabilisation

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26
Q

What is MOMP mediated by?

A

BCL2 associated X, apoptosis regulator (BAX) and/or BCL2 antagonist/killer (BAK)

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27
Q

Where are BAX and BAK located?

A

In cells, BAX continuously travels between the outer mitochondrial membrane and the cytosol in its inactive form. BAK is located within the outer mitochondrial membrane.

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28
Q

During induction of apoptosis, what happens to BAX and BAK?

A

BAX no longer retranslocates, and BAX and BAK are directly or indirectly activated by pro-apoptotic proteins, including BID and BAD.

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29
Q

Once BAK BAX, BID and BAD have been activated (by pro-apoptotic proteins) what apoptogenic factor is released?

A

Cytochrome C

And others

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30
Q

What is the second mitochondrial activator of caspases?

A

SMAC

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31
Q

Cytochrome C binds to _____________ and pro-caspase 9 to form the _____________, which is responsible for activation of caspase 9.

A

apoptotic peptidase activating factor 1 (APAF1)

supramolecular complex apoptosome

32
Q

What does activation of caspase 9 catalyse?

A

Proteolytic activation of the executioner caspase 3

33
Q

How does SMAC regulate apoptosis?

A

By associating with the inhibitor of apoptosis (IAP) protein family.

34
Q

Once executioner caspases are active, what morphological and biochemical changes occur?

A

DNA fragmentation, phosphatidylserine (PS) exposure, and the formation of apoptotic bodies. DNA fragmentation occurs by caspase 3 catalysing the proteolytic inactivation of DNA fragmentation factor subunit alpha (also known as ICAD - Inhibitor of CAD) and releasing the catalytic activity of CAD (Caspase-Activated DNAse )

35
Q

What is Anoikis?

A

A specific variant of intrinsic apoptosis and is initiated by the loss of integrin-dependent attachment to the extracellular matrix

36
Q

Where is cytochrome C normally found?

A

Inside the mitochondrion

37
Q

Define necrosis

A

Non-genetically programme cell death

38
Q

Define mitotic catastrophe

A

Failure of cells to undergo mitosis due to chromosome damage

39
Q

Define senescence

A

Metabolically active but unable to divide

40
Q

Define autophagy

A

Genetically programmed self-digestion, caspase- and p53-independent

41
Q

Which of the below molecules are extrinsic or intrinsic apoptotic pathway?
MOMP
DED
Casp-8

A 
MOMP: Intrinsic 
BID: Intrinsic
BAX: Intrinsic
Cas-9: Intrinsic
DED: Extrinsic
FADD: Extrinsic
TRADD: Extrinsic
Casp-8: Extrinsic
TNFR: Extrinsic
42
Q

Name the oncogenes involved in apoptosis

A

Akt, Bax, Cdk-4, Notch, B-Raf, Ras, PI3K

43
Q

Name the tumour suppressor genes involved in apoptosis

A

Bcl2, PTEN, BRCA1, p53, APC, Retinoblastoma

44
Q

What is p53 and what does active p53 mediate?

A

p53 is a transcription factor that governs anti-proliferative cell programmes, like cell cycle arrest, senescence, and apoptosis.

45
Q

Through anti-proliferative cell programmes, like cell cycle arrest, senescence, and apoptosis what does p53 facilitate?

A

Repair and survival of damaged cells or eliminates severely injured cells

46
Q

Which two apoptotic pathways can p53 activate?

A

Cells undergoing apoptosis via the p53-dependent mechanism mainly follow the ‘mitochondrial pathway’, but p53 can also activate ‘death receptor mediated apoptosis’.

  • cytosolic
  • mitochondrial
47
Q

In the cytosolic p53 pathway, nuclear p53 induces activation of which proapoptotic genes?

A

Including members of the BCL-2 family, like BAX, NOXA, and PUMA

48
Q

Following the release of proapoptotic genes (BAX, NOXA and PUMA) what happens to cytosolic p53?

A

This releases cytosolic p53 from the inactive complex with BCL-XL, and allows it to induce Bax oligomerization and mitochondrial translocation.

49
Q

Once cytosolic p53 is inside the mitochondria, what does it promote and block?

A
  • Bax and Bak activation

- blocks anti-apoptotic BCL-2 and BCL-XL

50
Q

Following uptake of cytosolic p53 into the mitochondria, what complexes with?

A

cyclophilin D, a protein responsible for mitochondrial permeability

51
Q 
Following:
complexing with cyclophilin D
BAX and BAK activation 
Blocking of BCL-2 and BCL-XL
What happens next?
A

Disruption of the mitochondrial membrane and release of cytochrome c (along with other apoptogenic factors), which consequently activates caspase 9.

52
Q

What happens during death receptor mediated apoptosis?

A

p53 overexpression, promoting Fas levels, which activate DR5 (Death Receptor 5), and promote cell death through caspase-8.

53
Q

What is p53 encoded by?

A

TP53: which is the most frequently mutated gene in human cancers, with over 50% of human cancers carrying loss of function mutations in TP53 genes

54
Q

Wild-type p53 is a classic __________, mutant forms of p53 can act as _______, by inhibiting wild-type p53 in a dominant-negative manner.

A

tumour suppressor

oncogenes

55
Q

What can cancer-derived mutant forms of p53 activate?

A

Various growth-promoting and oncogenic genes, including c-myc, multiple drug resistance gene 1 (MDR1), epidermal growth factor receptor (EGFR), and telomerase reverse transcriptase (TERT).

56
Q

Explain the dominant-negative effect of mutant p53 on wild-type p53

A

Pro-apoptotic function of p53 is significantly inhibited by certain p53 mutants which induce malignant transformation through up-regulation of c-myc and TERT

57
Q

Cells with mutated p53 have what 4 characteristics?

A

1) Less sensitive to DNA damage-induced apoptosis
2) Chromosome damage
3) Low oxygen (hypoxia) protection
4) Anoikis protection

58
Q

Apart from p53 mutation, other anti-apoptotic alterations can occur in cancers. What do they include?

A 
P14ARF inactivation
MDM2 overexpression
BAX mutation
BCL-2 overexpression
NFkB activation
PTEN activation
IGF-1/2 overexpression
FLIP overexpression
FAP-1 overexpression
59
Q

In normal cells, loss of attachment to the extracellular matrix would result in what?

A

Anoikis

60
Q

What mechanisms have cancer cells acquired to be able to evade anoikis?

A
  1. Hyperactivation of receptor tyrosine kinases (RTK)
  2. Apoptotic signalling
  3. Cytoskeletal rearrangement sensing
  4. Oxidative stress
  5. Autophagy
  6. EMT
61
Q

Explain hyperactivation of receptor tyrosine kinases (RTK) as a mechanism for evading anoikis

A
  • Cancer cells secrete growth factors that constitutively activate pro-survival signals, including PI3K, Ras-Erk, or Rho GTPase
  • Overexpression of RTK – ERBB2, which inhibits pro-apoptotic protein Bim, while maintaining EGFR expression
62
Q

Explain apoptotic signalling as a mechanism for evading anoikis

A

Cancer cells activate anti-apoptotic BCL-2 proteins

63
Q

Explain cytoskeletal rearrangement sensing as a mechanism for evading anoikis

A

Cancer cells undergo epigenetic silencing of adhesion-related genes, like the Src family member p66Shc, which results in Ras hyperactivation and RhoA inactivation

64
Q

Explain oxidative stress as a mechanism for evading anoikis

A

Oncoproteins, like ErbB2, bypass the metabolic stress induced by production of reactive oxygen species (ROS) during cell detachment. Increased antioxidant responses driven are further driven by upregulation of heme oxygenase 1 (HMOX1)

65
Q

Explain autophagy as a mechanism for evading anoikis

A
  • Autophagy is a lysosomal self-digestion
    Cancer cells initiate a protective autophagy, for example to allow them to become dormant during unfavourable conditions (like lack of nutrients)
  • During detachment, activation of autophagy in cancer cells contributes to glycolysis and cell proliferation
66
Q

Explain EMT as a mechanism for evading anoikis

A
  • activation of epithelial-to-mesenchymal transition (EMT)

- upregulation of matrix metallopeptidases (MMPs)

67
Q 
Name the:
1) trigger initiating the apoptosis
2) proteins driving the process
3) activated caspases 
For the INTRINSIC death pathway
A

1) microenvironmental trigger, e.g. DNA damage or withdrawal of growth factors
2) controlled by pro-apoptotic (like BID, BAD, BAX) and anti-apoptotic (like Bcl-XL) BCL2 family proteins, release of apoptogenic factors (like cytochrome 3), which bind to pro-caspase 9 and form apoptosome
3) Caspase 9 and caspase 3

68
Q 
Name the:
1) trigger initiating the apoptosis
2) proteins driving the process
3) activated caspases 
For the EXTRINSIC death pathway
A

1) binding of death ligand to death receptor (e.g. FAS to FASL)
2) formation of death-inducing signalling complex (DISC) composed of FADD (binding of DD with DED) interacting with pro-caspase 8
3) Caspase 8 and caspase 3

69
Q

How do you promote intrinsic apoptosis in cancer cells ?

A

Interfere with the cyto-protective effects of antiapoptotic members of the BCL-2 family via:

1) Interference with mRNA function
2) Development of small-molecule drugs to target specific proteins
3) Shut down gene transcriptions

70
Q

Explain interference with mRNA function as a method of promoting intrinsic apoptosis in cancer cells

A

To interfere with mRNA function antisense oligonucleotides (ASOs) are used. ASOs are short synthetic sequences of single-stranded DNA that can bind to target mRNA. They act by enhancing sensitivity to cytotoxic drugs. One of the ASOs that is advanced in clinical settings is oblimersen sodium (G3139, Genasense), which is an anti-BCL-2 mRNA agent, and is currently used in clinical trials for lymphoma.

71
Q

Explain the development of small-molecule drugs to target specific proteins as a method of promoting intrinsic apoptosis in cancer cells

A

Small-molecule inhibitors of the BCL-2 protein family include those targeting histone deacetylases (HDACs), which control gene expression. Currently, there are two approved HDAC inhibitors: vorinostat and romidepsin, against refractory cutaneous T-cell lymphoma (CTCL), while over 350 clinical trials have been completed or are underway using HDAC inhibitors.
Other approach includes both natural and synthetic BH3 mimetics to induce apoptosis. These mimic critical domains of pro-apoptotic members of the Bcl-2 family, which include Bax and PUMA. Highly promising BH3 mimetics therapy was recently approved by FDA for the treatment of 17p‑deleted chronic lymphocytic leukaemia (CLL).

72
Q

Explain shut down gene transcription as a method of promoting intrinsic apoptosis in cancer cells

A

Small-molecule inhibitors can also act by targeting Inhibitors of Apoptosis (IAPs) by mimicking SMAC or by antisense-mediated interference of XIAP mRNA and protein expression

73
Q

In the extrinsic pathway, what did early efforts of targeting apoptosis in cancer cells include?

A
  • purified TNF-α: to target one of the death receptors TNF
  • activate the second death receptor, FAS
  • targeting of another death ligand, TNFSF10 (also called Apo2L/TRAIL)
74
Q

Why is promoting the extrinsic death pathway of cancer cells by purified TNF-α not used clinically?

A

It was too toxic for systemic therapy.

75
Q

Why is promoting the extrinsic death pathway of cancer cells by activating the second death receptor, FAS, not used clinically?

A

Too toxic, with excessive apoptosis of liver cells, hepatocytes

76
Q

What did targeting of another death ligand, TNFSF10 (also called Apo2L/TRAIL) result in?
What limits the efficacy?

A

More success and the creation of TNFSF10 cognate proapoptotic death receptors DR4 and DR5 antibodies. These antibodies are better tolerated but resistance is common which limits the efficacy in monotherapy or in a combined therapy with conventional treatments.

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