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Cancer mechanisms and therapeutics > Inflammation in cancer > Flashcards

Inflammation in cancer Flashcards

1
Q

What is the irritation theory of cancer?

A
  • chronic inflammation increases cancer risk
  • subclinical inflammation such as that caused in obesity also
  • immune and inflammatory cells are seen within tumours and the same pathways seen in wound healing are also seen in cancer
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2
Q

What is colitis associated cancer?

A
  • drives 2-3% of colorectal cancer in teh UK
  • cells in the crypt are inflamed and produce cytokines, ROS and nitric oxide that can drive tumorigenesis
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3
Q

How/why does inflammation drive cancer formation?

A
  • promotes innate immunity
  • NFkB plays a major role in innate immunity and the inflammatory response
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4
Q

What is NFkB?

A
  • a transcription factor that regulates inflammation and the immune response
  • stimulated by many inflammatory signals and cytokines such as TNF
  • plays an important role in cancer through cross-talk with other pathways such as p53 and Wnt
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5
Q

NFkB can be activate independently of de novo protein synthesis. WHy is this significant?

A
  • can rapidly respond to stimuli without waiting for the synthesis of new proteins
  • fast immune response or inflammation following stress
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6
Q

What are the core 5 NFkB genes in mammalian cells?

A

rel proteins
RelA
RelB
C-Rel
and the NFkB proteins p105/p50 and p100/p52

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7
Q

Describe the structure of Rel proteins

A
  • Rel homology domain at the N terminus
  • transcription domain at the C terminus
  • RelB also had a leucine zipper at the N terminus
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8
Q

Describe the structure of NFkB proteins

A
  • rel homology domain at the N terminus
  • glycline-rich region at the c terminus
  • short and long protein versions
  • in the long version, GRR binds ankyrin repeat domains that act as inhibitors of NFkB signalling and activation
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9
Q

Why is the rel homology domain of NFkB and rel proteins critical for their function?

A
  • contain a DNA binding domain and a dimerisation domain
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10
Q

How do rel/NFkB proteins regulate transcription?

A
  • rel domains contain transactivation domains and can bind DNA and regulate transcription independently
  • p50 and p52 need to dimerise with other family members to form transactivating DNA binding proteins
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11
Q

Describe NFkB subunit dimerisation

A
  • can all dimerise with eachother in 15 formations
  • two main heterodimers
  • p50;RelA and RelB:p52
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12
Q

What are the two main pathways of NFkB signalling?

A
  • canonical pathway (RelA:p50) involved in innate immune regulation involves TNF, TLRs and growth factor receptors
  • non-canonical pathway (RelB:p52)
  • immune cell function and maturiy involves CD40 and lymphotoxin beta receptors
    Both pathways result in different NFkB phenotypes in the cell
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13
Q

Describe the basic steps of activation of canonical signalling

A
  • ligand-receptor binding
  • activation of intracellular IKK complex
  • degradation of inhibitory complexes (IKBs)
  • nuclear translocation of NFkB dimer (RelA:p50) and DNA binding
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14
Q

What is the role of TNF signalling in cell survival?

A
  • TNF receptor trimierises upon binding with TNF extracellularly
  • signals two intracellular pathways and genes
    AP1 causes apoptosis
    or RealA:p50 causes survival
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15
Q

What happens at the TNF receptor to trigger apoptosis?

A
  • SODD sits on the TNF receptor death domains and stops their signalling
  • TNF binds and SODD is released
  • TRADD can now bind the death domains and form a TRADD-associated signalasome that binds FADD and TRAF leading to NFkB signalling. FADD can also activate AP1 to cause apoptosis
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16
Q

What happens when TRAF binds the TRADD associated signalasome?

A
  • TRAF binds RIP1 and leads to its non-degradative polyubiquitination
  • ubiquitin chain recruits IKK complex into the large complex attached to the TNF receptor on the cell membrane
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17
Q

What is the IKK complex?

A
  • complex of 3 proteins - IKK-alpha, IKK-beta and NEMO
  • NEMO has no kinase domain so doesn’t cause intracellular phosphorylation but acts as a scaffold for the canonical complex to form by its ubiquitin-binding domain
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18
Q

What happens once the IKK complex is brought into the TRAFF-TRADD associated signalasome complex?

A
  • NEMO facilitates the phosphprylation of IKK-B and results in its autophosphorylation and upregulation
  • this leads to phosphorylation of IKB-alpha and IKB-beta
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19
Q

What happens when IKB-alpha and IKB-beta are phosphorylated?

A
  • they are ubiquitinated and degraded and released from the RelA:p50 dimer
  • IKB-a usually sits on the NLS so their removal means that the heterodimer can now translocate to the nucleus
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20
Q

What are the IKB proteins?

A
  • IKB-alpha is the more important as it contains a nuclear export signal
  • their ankyrin repeat domains allow them to bind to Rel and NFkB proteins to inactivate NFkB signalling
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21
Q

Describe the negative feedback loop in the canonical signalling pathway

A
  • IKB sits over the RelA NLS
  • when degraded RelA can translocate to the nucleus with p50
  • the heterodimer binds the IKB-alpha promoter leading to its synthesis
  • IKB-alpha enters the nucleus and uses its NES to shuttle the heterodimer back out
22
Q

Other than IKBs, how else can negative feedback of NFkB signalling occur?

A
  • ubiquitination can be activating
  • deubiquitination can be inhibitory
23
Q

What is the basis of ubiquitin signalling?

A

ubiquitination on different lysines can cause different effects. can signal for degradation of act as signals

24
Q

How does deubiquitination inactivate NFkB signalling?

A
  • many enzymes can deubiquitinate RIP1 stopping the signalling to IKbs and the nuclear translocation of RelA:p50
  • Example is A20 the KO of which leads to persistent inflammation
25
Q

Describe the negative feeedback and occilations seen in canonical signalling i more detail

A
  • RELA;p50 causes the de novo protein synthesis of IKB-a which is made in the cytoplasm
  • when not bound to dimers, it doesnt get phosphorylated and degraded and so is free to move into the nucleus and bind Rela:p50 and use its NES to shuttle it back out
  • once it enters the cytoplasm, IKB-a can be degraded again, starting the signal over again
  • at the initial TNF binding there is a peak in expression as all cells do this but they then begin to lose synchonoicty as tme goes on due to them having different levels of IKB-a that does this at different rates
  • the speed at which these occilations in and out of the nucleus occur, along with how long the occilations occur for is part of what determines NFkB signal following activation.
26
Q

How does post-translational modification of NFkB (RelA:p50) occur?

A
  • when released from IKB
  • NFkB gets phosphorylated by PKA to enhance its DNA binding providing an interaction site for CBP acetylase
27
Q

What happens when p50:RelA binds CBP

A
  • acetylation of lysine residues forms a code for signalling
  • if on K130 it allows full transcriptional activity
  • on K221 it leads to a prolonged response without shuttling in and out of the nucleus
  • on K122 it leads to faster termination and shuttling back to the cytoplasm
28
Q

How is chromatin remodelling involved in canonical NFkB signalling?

A
  • CBP can also acetylate histones local to NFkB binding sites
  • can widen partial binding sites
  • the p50 homodimer is often bound to HDACs and leads to transcriptional repression
29
Q

How does Bcl-3 act as a co-factor to NFkB canonical signalling?

A
  • binds p50 homodimers and causes dimer switching by removing p50 dimers and promoting the formation of RelA:p50 heterodimers to increase transcription.
  • other cofactors exist and can be promoting or repressing based on their stimulus
30
Q

Describe NFkB binding affinity

A
  • NFkB is found in most cell types and its consensus sequence is very common
  • it can also bind to half sites or those that are slightly incorrect
  • different dimers have different binding affinity to DNA for example RelA:p50 heterodimers have a higher affinity than p50 homodimers
31
Q

Other than dimer conformation, what else can affect NFkB binding affinity to DNA? (3)

A
  • consensus sequence - different consensus sequences lead to different NFkB functions
  • protein modifications
  • co-factor presence
32
Q

What is the non-canonical pathway of NFkB signalling?

A
  • RelB dimierises with p100 in the cytoplasm and becomes RelB:p52 after processing
  • can be both active and repressive and drives its own transcription and negative feedback
  • can block the binding of canonical dimers important in development of lymphoid organs
33
Q

What is NIK?

A
  • NFkB-inducing kinase
  • in unstimulated cells its bound to TRAF and ubiquitinated being constantly produced and degraded
34
Q

What happens to NIK following stimulation of the non-canonical pathway?

A
  • TRAF is taken up by the receptor and degraded instead
  • NIK is activated and activates IKK-alpha that phosphorylates p100 into p52
35
Q

How is p105 processed in the canonical pathway?

A
  • into p50
  • constitutively processed the moment it is produces and immediately forms dimers with RelA
36
Q

What is atypical NFkB activation?

A
  • dimers other than RelA:p50 and Relb:p52
  • can sit on NFkB consensus sites and drive transcription
  • most common are p50 and p52 homodimers
  • these can be repressive and block the binding of transactivating NFkBs
  • poorly understood
37
Q

What kinds of signals are affected by NFkB signalling?

A

those in survival, proliferation, tumour promotion, angiogenesis and inflammation

38
Q

What is the inflammasome?

A
  • collection of receptor base complexes that form as a result of binding of ligands
  • control innate immuntity and the microbiota
  • for example the NLRP3 inflammasome
39
Q

What are DAMPs and PAMPs?

A
  • damage/pathogen associated molecular patterns
  • proteins produced by damage or pathogens that signal to cells and drive the formation of inflammasomes
40
Q

How is the NLRP3 inflammasome activated?

A
  • driven by DAMPs/PAMPs
  • NLRP3 binds ASC proteins and aggregate
  • binds CARD leading to cleavage of pro IL-18 and pro IL-B activating inflammatory signalling pathways
41
Q

What are the two types of inflammasome signals?

A
  • signal 1 comes form PAMPs that bind TLR4, activate NFkB and leads to the transcription of caspases and preforms of proinflammatory cytokines
  • signal 2 comes from DAMps and leads to the formation of the inflammasome and the cleavage and activation of caspases and cytokines leading to pyroptosis and inflammation
42
Q

How can NFkB contribute to cancer?

A
  • constitutive activation can be antiapoptosic and pro-proliferative and is seen in many tumours
  • can also regulate genes involved in drug metabolism and lead to resistance and radiation resistance
43
Q

How does NFkB and Wnt crosstalk contribute to cancer?

A
  • active IKK beta increases B-catenin translocation to the nucleus in the colon upregulating Wnt signalling
  • these are the earliest events that lead to colon cancer
  • an increase in DNA damage leads to higher mutation rates, loss of heterozygosity and tumours
44
Q

What does B-catenin do to NFkB?

A
  • increased B-catenin due to tumourigenesis drives NFkB activation
  • IKB alpha is phosphorylated by active B-catenin rapidly
  • creates a positive feedback loop
45
Q

What crosstalk between NFkB and p53 occurs?

A
  • p53 is upregulated by stress signals
  • NFkB is upregulated by survival signals
  • their consensus sites are close and there can be competition for binding
  • they also compete for cofactors such as CBP
  • strong survival signals lead to more NFkB in the nucleus and outcompetes p53 and vice versa
46
Q

What is the role of ATM following DNA damage?

A
  • gets phosphorylated following damage
  • phosphorylates CHK2 which phosphorylates p53 and stops it binding MDM2 allowing repair or apoptosis
47
Q

How is ATM linked to NFkB?

A
  • ATM knockouts stops NFkB signalling
  • therefore ATM must be required
  • also drives genotoxic stress induced activation of NFkB
48
Q

How can DNA damage directly induce NFkB signalling?

A
  • dependent on NEMO
  • binds IKK-a or IKK-b or gets sumoylated and binds ATM
  • results in phosphorylation of NEMO, ubiquitination and the activation of IKK complex and canonical pathway
49
Q

What happens when Bcl-3 is knocked down?

A
  • Bcl-3 is an aytipical IKB
  • increases sensitivity to gamma radiation
  • reduces repair and leads to increased cell death
  • Bcl-3 binds the p50 homodimer and acts as a cofactor for HATs and HDACs
50
Q

5

What kinds of drugs can interfere with NFkB signalling?

A
  • nuclear pore inhibitors to stop the movement of dimers
  • IKK inhibitors like asprin (side effects)
  • proteasome inhibitors stop IKB-a degradation
  • DNA binding inhibitors
  • monoclonal antibodies to block TNF receptors
  • all treatments are nonspecific with off target effects
51
Q
A

Cancer mechanisms and therapeutics (12 decks)

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