Apoptosis Resistance in cancer Flashcards
What is the death receptor pathway of apoptosis?
- ligand binds to death receptors and molecules such as FADD are recruited
- recruits caspses such as 9+8 that are recruited into a complex inside the cell to form a death inducing signalling complex (DISC)
Name some death receptors, their ligands and their roles
Describe the premise of death receptor signalling
- death ligand binds death receptor
- recruits adapter proteins
- recruit initiator and effector caspases
- apoptosis or activation of signalling molecules susch as NFkB and MAPK lead to survival
Describe fas induced apoptosis
- fas ilgand binds best as a timer
- activates intracellular death domain
- recruits FADD due to their shared homology
- this recruits procaspase 8 that activates effector caspases in type I cells or cleaves Bid in type II cells
What are type I cells in the context of fas induced apoptosis?
- cells that do not need Bid for fas mediated cell death
- such as lymphocytes
What are type II cells in the contect of fas induced apoptosis?
- cells that use BID to amplify fas induced death signals by release of cytochrome C
- Bcl-2 can block death rceptor induced apoptosis in type II cells only
- hepatocytes
What kinds of cancers are caspase 8 mutations commonly seen in?
- gastric and hepatocellular
- C8 mutant cells are more resistant to apoptosis
- those with these mutations have lower survival
What is ALPS?
- autoimmune lymphoproliferative syndrome
- point mutations in death domain leads to a truncated fas receptor that cant recruit DISC components
- leads to increased risk of lymphomas
What are decoy receptors?
- death receptors with no intracellular death domain
- mop up death ligand and stops it binding functional receptors
- can be solubule
- can be overexpressed in cancer such as colon cancer
How does fas ligand expression change as cells move towards a cancer phenotype?
expression increases during progression from adenoma to carcinoma to metastasis
Describe fas in colon tumours
- tumours usually resistant to induction of fas-mediated apoptosis
- but produce their own soluble fas ligans during progression that harms the cells around them
- (cell competition)
What is cFLIP?
- structurally similar to caspase 8 but no proteolytic activity
- blocks death receptor signalling by docking onto adapter molecules and integrating into the DISC to reduce caspase recruitment
- high levels in malignant melanoma and colon cancer
What is the benefit to cancer cells in producing high levels of fas ligand?
- allows them to develop as immune privileged sites by inducing apoptosis of activated infiltrating T cells that express fas
- counter attack
What are the consequences of fas ligand expression by tumours?
- facilitates metastatic colonisation of fas-sensitive organs by inducing apoptosis of these cells
- enhances cancer cell proliferation and invasion as they have more space to move into
Give an example of a fas-sensitive organ
liver
How can the immune system induce apoptosis?
- CD8+ T cells in adaptive
- NK cells in innate
- kill cells through the fas pathway or through the granule exocytosis pathway
What is the calcium dependent granule exocytosis pathway?
- lumphocytes secrete perforin that creates pores in the plasma membrane of the target cell
- granzymes (serine proteases) can then produce tBid and induce apoptosis
In summary, name 4 ways in which tumour cells can become resistant to fas mediated apoptosis
- receptor mutation
- reduced receptor expression
- overexpression of cFLIP
- overexpression of Bcl-2 in type II cells
How can proapoptotic BH3 only proteins be regulated?
- by cleavage into tBID
- regulated by transcriptional mechanisms, phosphorylation or cell matrix detacthment
What happens in the cell when survival factors are present?
- PI3K activates Akt
- Akt phosphorylates Bad, inactivating it and allowing it to be sequestered by the 14-3-3 protein
What happens to Bad when survival factors are depleted?
- Akt is no longer activated
- Bad isnt phosphorylated and remains active to act as a BH3 protein
- Bad displaces Bcl2 family members leading to apoptosis
What are Bmf and Bim?
- BH3 only proteins
- at high levels in normal cells but sequestered
- recognise when cells detach from the ECM due to their links with microtubules
- triggers apoptosis
- Bmf is expressed in non-invasive breast tumours but commonly lost when they become metastatic
What is BIM and what its isoforms?
- Bcl-2 family member
- BIM-EL is most common
- BIM-S least common
What does BIM do?
- normally proteasomally degraded in the ras pathway
- when growth factors are depleted, BIM binds MCL-1, displacing Bax and allowing apoptosis
- mutations in ras - always displacing Bax
What are direct activators?
- BH3 only family proteins that can bind directly to Bax, Bak and initiate their oligomerization without having to displace it from Bcl-2
- Bad can only activate them with this displacement and is known as a sensitiser
What are the different antiapoptotic potencies?
- Bcl-2, XL have greater antiapoptotic capcity then others due to their greater stability
- these have half lives of ~20 hours
- other proteins may only last 1-4 hours
What else is released from the mitochondria to trigger apoptosis?
- apoptotis inducing factor and enconuclease A
- these cause DNA fragmentation when other pathways are lost
- SMAC/DIABLO + OMI inhibit XIAP and release proapoptotic caspases
What are IAPs?
- human inhibitor of apoptosis proteins
- XIAP, survivin etc
What is the role of XIAP?
- IAP that binds caspases and inhibits them by targeting them for proteosomal degradation
- can also promote NFkB activation
What is survivin?
- IAP overexpressed in almost all human cancers
- low/undetectable levels in normal tissues
- promotes cell survival and affects mitotic transition
- increased in tumours cells by PI3K and B-catenin pathways
