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Cancer Mechanisms and Therapeutics > Apoptosis Resistance In Cancer > Flashcards

Apoptosis Resistance In Cancer Flashcards

1
Q

Which caspase does FADD recruit in Fas signalling

A

Caspase 8

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2
Q

What happens in type 1 cells of Fas signalling

A

Caspase activation

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3
Q

What happens in type 2 cells of Fas signalling

A

Cleavage of bid by caspase 8 –> leads to the intrinsic pathway of apoptosis

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4
Q

Example of type I cells

A

Lympocytes

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5
Q

What is the disorder that occurs due to Fas mutations

A

ALPS –> Autoimmune lymphoproliferative syndrome

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6
Q

What % of colon tumours is fas altered in

A

Fas receptors are downregulated in 50% of colonic tumours

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7
Q

What pathways can Fas signaling activate

A

Jak/Stat
Ras
NFkB
PI3K

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8
Q

What is FLIP

A

Structurally similar to caspase 8 but no proteolytic activvity !!

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9
Q

What are the 2 mechanisms of killing of cytotoxic T cells

A

1) Death receptor signalling i.e. Fas pathway

2) Granule exocytosis pathway

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10
Q

What pathway leads to bad phosphorylation

A

Survival signalling i.e. Il-3 causes PI3K/Akt activation –> phosphorlates Bad

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11
Q

What protein sequeusters phosphorylated bad

A

14-3-3 protein!

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12
Q

Which 2 apoptosis proteins play a role in anoikis

A

Bim and Bmf

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13
Q

What is anoikis

A

Anoikis is apoptosis induced by inappropriate or inadequate cell-matrix interactions

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14
Q

What role does Bim have in anoikis

A

Bound to microtubules via DLC-1 and dynein motor complex

Changes in interactions releases the BH3 proteins and can cause apoptosis

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15
Q

What role does Bmf have in anoikis

A

Bound to actin via DLC-2 and the myosin IV motor complex

Changes in interactions releases the BH3 proteins and can cause apoptosis

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16
Q

how many forms of Bim are there

A

3

a) Bim-Xl
b) Bim-L
c) Bim-s

17
Q

Which BH3 proteins are sensitisers Only

A

Bad and Noxa

18
Q

Which BH3 proteins are direct activators

A

Bim, tBid, Puma

19
Q

What other products does the mitochondria release along with cytochrome C

A

Apoptosis Inducing Factor
Endonuclease G
Smac/Diablo
OMI

20
Q

What caspases does CIAP inhibit

A

9, 3, 7

21
Q

What pathways upregulate survivn

A

PI3K

Wnt/B-catenin

22
Q

Actions of Survivin

A

Binds and inhibits smac/diablo
Synergistic effect on XIAP
Also potent activator of NF-kB

23
Q

What structural features defines the death receptors

A

Cysteine rich extracellular domain

Have an intracellular 80 a.a. death domain

24
Q

What TRAIL Receptors are frequently decoys

A

Trail 3-5

25
Q

What drug can cause functionally active CD95L and cayse death in T cell leukaemia

A

Doxorubicin!

26
Q

What tumours often display downregulated CD95

A

Leukaemias and nueroblastomas

Often also get TRAIL silencing seen in many tumours thoguh loss of heterozygosity or epigenetic silencing

27
Q

How and which caspase is altered in neuroblastomas

A

Caspase 8 through hypermethylation of the promoter.

28
Q

What are some of the targets of NFkB Transcription

A

FLIP
IAPs
BCL-xl

29
Q

Name some tumours in which NFkB is constituitively active

A

Hodgkins lymphomas

Pancreatic carcinomas

30
Q

Which tumour is FLIP Shown to be high in

A

Burkitt’s lymphoma

31
Q

Was CD95 agonists shown to be good

A

NO –> through to have at least some therapeutic use BUT had lethal effects as caused death in lots of hepatic cells!!!

32
Q

Why does TRAIL appear to be a promising anti-cancer target

A

No cytotoxicity

But some tumours may have resistance due to upregulation of anti-apoptotic signalling

33
Q

What can we combine TRAIL With to increase its efficact in cancer treatement

A

Combine with small moleculue inhibitor I.E. Smac-agonists –> potentiate TRAILs effects as inhibits IAPs which is overexpressed in many tumours

34
Q

How does phosphorylations of p53 affect whether apoptosis or cell sensecence occurs

A

Phoshphorylation of p53 at Ser46 leads to cytochrome C release and apoptosis

35
Q

Wht can p53 upregulate that contributes to apoptosis

A 
p21 - a CDKI
Fas
ARAF-1 --> is a p53 target gene
PTEN - a phosphatase
PIDD - a cytoplasmic death domain that ican activate caspase 2
BAc
Bid
NOXA AND PUMA
36
Q

How does PTEN stop p53 degradation

A

Antagonist of AKT-phopshorylatio of MDMs

37
Q

Is p53 upregulating Bim shown to be key to apoptosis

A

NO mutated forms of p53 can upregulate BIM as well, hence doesnt seem to be a transcriptional dependent increae.

38
Q

Which BH3 protein is importantly linked to p53 apoptosis

A

PUMA –> p53 can upregulate Puma and has been shown to be essential for p53 apoptosis in many cell types!

Cancer Mechanisms and Therapeutics (10 decks)

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