Prostaglandins and Wnt Signalling In Cancer Flashcards
Which prostaglandin cause the pro-tumorigenic effects
PGE2
What are the 6 hallmarks of cancers
1) Self sufficiency in growth signals
2) Resistance to anti-growth signals
3) Evading Apoptosis
4) Limitless replication potential
5) Tissue invasion and metastasis
6) Angiogenesis
How does COX influence self sufficiency in growth signalsd
Ras-raf-mek-erk pathway
How does COX influence resistance to anti-growth signalds
Resistance to TGF-beta signalling
How does COX influence evading apoptosis
Cox reduces the amount of arachadonic acid that can convert sphingomyelin to ceramide
COX increases bcl2 and decreases bim
How does COX influence limitless replication potential
Enhances beta catenin signalling
How does cox influence tissues invasion and metastasis
HCF and c-met signalling
Also altered metalloproteinases and modulates the cell adhesive properties
How does COX influence sustained angiogenesis
Increases VEGF and FGF
How does prostaglandings influence the PI3K AKT Pathways
Ultimately inhibits GSK3B
Inhibits BAD
How does ras-raf-mek-erk pathway be affected by COX
Inhibits Bim
Phosphorylates and stabilised c-myc
Which EP receptor for COX is most associated with tumorigenesis
EP4
How does cAMP/PKA influence B-catenin through COX
PGE2 bings to EP2/4 receptor
Alpha subunit activates cAMP
cAMP activates PKA
PKA phosphorylates GSK3B and Ser 9 and Beta-catenein at Ser675
How does PI3K/AKT influence beta-catenin through COX
PGE2 binds to EP2/4 receptor
Alpha subunit swaps GDP for GTP and dissociates to bind to axin –> disrupts the destruction complex
Beta and gamma subunit stimulate the PI3K/AKt pathway which causes GSK3B phosphorylation and stimulation
How does COX Influence the Ras-Raf-Mek-Erk pathway and Bim
PGE2 activates Ras-Raf-Mek-Erk Pathway
ERK Phosphorylates Bim at Ser 69
RSK can then subsequently phosphorylate it at SER 93, 94, 98
THen allows phosphorylation by BetaTrCP
How can NSAIDS affect Bim expression
Can induce Bim expression in CRC cells and may aaccount for the chemopreventative effects
Why do NSAIDS not induce apoptosis in all cancer cells if they increase Bim expression
As cancer cells can overexpress pro-survival memebers of the bcl-2 family
How can we overcome the problem of cancer cells over-expressing Pro-survival members of the bcl-2 family when COX-2 is also bein produced
Combine NSAIDS with a drug to inhibit pro survival BCl-XL e.g. Navitoclax
What drug can inhibit bcl-2 family members
Navitoclax e.g. ABT-263
Whatt transcriptionally affects Bim expression
FOXO3a expresion increaese Bim expression
What post-translationally affects Bim expressoin
ERK mediated phosphorylation
How is Bim affected by the PI3K pathway
Also negatively regulates Bim
BRAF Mutatant allele is sufficient to repress Bin Expressionq
What has Addiction to Bim repression been seen in
Haematopoietic tumour cells
Melanomas and CRC with BRaf mutations
WHere has Bim been shown to be epigenetically silenced
Renal cell carcinomas
WHy can we not use long term selecive cox-2 inhibitors
Incrases risk of CV events
