Cell death and cancer Flashcards
What 3 mechanisms cause cell death?
- necrosis - most common cause - occurs due to ischemia, trauma, chemical injury
- apoptosis - programmed cell death, designed to eliminate unwanted host cells through activation of co-ordinated programmed series of events
- autophagic cell death - autophagy is responsible for the degradation of normal proteins involved in cellular remodelling found during metamorphosis, ageing and differentiation as well as for the digestion and removal of abnormal proteins - that would otherwise accumulate following toxin exposure, cancer or disease - eg death of breast cancer cells by tamoxifen
What are the function of apoptosis?
- selective process for the deletion of superfluous infected or transformed cells
- involved in embryogenesis, metamorphosis
- normal tissue turnover
- endocrine-dependent tissue atrophy
Examples of apoptosis
- cell death of embryonic hand = individual fingers
- cell death in tumours causing regression
- cell death in viral diseases
- death of neutrophils during a acute inflammatory response
How is apoptosis induced?
- UV and gamma radiation
- chemotherapeutic drugs
- growth factor withdrawal
- cytokines eg. TNF alpha
- loss of extracellular matrix
What are the two types of apoptosis?
Intrinsic - DNA damage - p53 - interruption of cell cycle - inhibition of protein synthesis - viral infection - change in redox state Extrinsic - withdrawal of growth factors - extracellular signals - T cells or NK killing
What are caspases?
- cysteine aspartate-specific proteases
- play central role in initiation of apoptosis
- most proteases are synthesised as inactive precursors requiring activation
- their activation leads to characteristic morphological changes of the cell such as shrinkage, chromatin condensation, DNA fragmentation and plasma membrane blebbing
What are some substrates for caspases?
lamin A and B = nuclear envelope
PARP = DNA repair
DNA-PK = DNA repair
topoisomerase II = DNA replication
What are the nuclear changes that occur during apoptosis?
- nuclear chromatin condenses on nuclear membrane
- DNA cleavage
What are the cytoplasmic changes that occur during apoptosis?
- shrinkage of cell, organelles packaged into membrane vesicles
- cell fragmentation - membrane bound vesicles bud off
- phagocytosis of cell fragments by macrophage and adjacent cell
- no leakage of cytosolic components
What are the biochemical changes that occur during apoptosis?
- expression of charged sugar molecules on outer and inner surface of membranes
- expression of phosphatidylserine on extracellular leaflet of apoptotic cell
- protein cleavage by proteases
How are initiator caspases activated?
- induced proximity
- eg in response to receptor dimerisation upon ligand binding
What are the key players in ligand-induced dimerisation?
- receptor (ligand binding)
- death adaptor - death effector domain
- death effector domain binds procaspase-8 (protease domain)
- TNF induces the formation of a death inducing signalling complex - DISC
How is cytochrome c involved in apoptosis?
- intrinsic pathway
- cytochrome c binds with APAF (contains cyt c binding site and caspase recruitment domain)
- then binds to procaspase 9
How is the release of cytochrome c regulated?
- anti-apoptotic and apoptotic signals bind - eg Bax anf bcl-2 - prevents cyt c being released
What is the bcl-2 family?
contains two families anti-apoptotic = bcl-2, blc-XL pro-apoptotic = Bax, Bak, Bid - can form dimers - bcl-2 + bcl-2 = life - bcl-2 + bad = life - bad + bad = death
What happens if the survival factors are removed?
- without survival signals = no kinases bind to Bad
- therefore the Bad molecule is not phosphorylated
- it is able to compete with Bax to bind to bcl-2
- if bad binds to bcl-2, it removes bcl-2 from the cyt c complex = DEATH
How can intraceullar stress lead to death of the cell?
- in response to DNA damage - p53 is released
- p53 activates expression of Bax
- increased expression of pro-apoptotic proteins
- Bax will forms bonds on mitochondrial membrane
- cyt c release bind to APAF/caspase-9 complex = death
How is apoptosis related to disease?
- cancer - breast, lung, kidney…
- neurological diseases - alzheimers, parkinsons
- cardiovascular disease - ischemia, heart failure
- autoimmune diseases - SLE, ALS
How does dysregulated apoptosis lead to cancer?
- disrupted balance of bcl-2 family of proteins
- reduced expression of caspases
- defects in p53
- impaired receptor signalling pathways
How does p53 and apoptosis induce cancer?
- inactivating mutations in the p53 gene = most common mutations in cancer
- sometimes destroy the ability of p53 to induce apoptosis
- eg HPV - viral E6 protein sequesters p53 and targets it for degradation
How does BCL-2 induce cancer?
- over expression - in Hodgkin lymphoma
- breast cancer - tumour aggressiveness, reduced survival and resistance to endocrine therapy
- under-expression = Bax and Bak mutations described in colon and gastric carcinomas
What are IAPs?
- inhibitors of apoptosis proteins
- eg, XIAP, survivin
- ability to suppress host cell response during viral infection
How is caspase activity altered?
- caspase alterations identified in a variety of tumours
- can be due to mutations, promoter methylation, alternative splicing
How do impaired signalling pathways lead to cancer?
- due to mutations, promoter methylation and alternative splicing
- in ALS
