Prostaglandins and Wnt Signalling In Cancer

Question 1

Which prostaglandin cause the pro-tumorigenic effects

Answer 1

PGE2

Question 2

What are the 6 hallmarks of cancers

Answer 2

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

Question 3

How does COX influence self sufficiency in growth signalsd

Answer 3

Ras-raf-mek-erk pathway

Question 4

How does COX influence resistance to anti-growth signalds

Answer 4

Resistance to TGF-beta signalling

Question 5

How does COX influence evading apoptosis

Answer 5

Cox reduces the amount of arachadonic acid that can convert sphingomyelin to ceramide
COX increases bcl2 and decreases bim

Question 6

How does COX influence limitless replication potential

Answer 6

Enhances beta catenin signalling

Question 7

How does cox influence tissues invasion and metastasis

Answer 7

HCF and c-met signalling

Also altered metalloproteinases and modulates the cell adhesive properties

Question 8

How does COX influence sustained angiogenesis

Answer 8

Increases VEGF and FGF

Question 9

How does prostaglandings influence the PI3K AKT Pathways

Answer 9

Ultimately inhibits GSK3B

Inhibits BAD

Question 10

How does ras-raf-mek-erk pathway be affected by COX

Answer 10

Inhibits Bim

Phosphorylates and stabilised c-myc

Question 11

Which EP receptor for COX is most associated with tumorigenesis

Answer 11

EP4

Question 12

How does cAMP/PKA influence B-catenin through COX

Answer 12

PGE2 bings to EP2/4 receptor
Alpha subunit activates cAMP
cAMP activates PKA
PKA phosphorylates GSK3B and Ser 9 and Beta-catenein at Ser675

Question 13

How does PI3K/AKT influence beta-catenin through COX

Answer 13

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

Question 14

How does COX Influence the Ras-Raf-Mek-Erk pathway and Bim

Answer 14

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

Question 15

How can NSAIDS affect Bim expression

Answer 15

Can induce Bim expression in CRC cells and may aaccount for the chemopreventative effects

Question 16

Why do NSAIDS not induce apoptosis in all cancer cells if they increase Bim expression

Answer 16

As cancer cells can overexpress pro-survival memebers of the bcl-2 family

Question 17

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

Answer 17

Combine NSAIDS with a drug to inhibit pro survival BCl-XL e.g. Navitoclax

Question 18

What drug can inhibit bcl-2 family members

Answer 18

Navitoclax e.g. ABT-263

Question 19

Whatt transcriptionally affects Bim expression

Answer 19

FOXO3a expresion increaese Bim expression

Question 20

What post-translationally affects Bim expressoin

Answer 20

ERK mediated phosphorylation

Question 21

How is Bim affected by the PI3K pathway

Answer 21

Also negatively regulates Bim

BRAF Mutatant allele is sufficient to repress Bin Expressionq

Question 22

What has Addiction to Bim repression been seen in

Answer 22

Haematopoietic tumour cells

Melanomas and CRC with BRaf mutations

Question 23

WHere has Bim been shown to be epigenetically silenced

Answer 23

Renal cell carcinomas

Question 24

WHy can we not use long term selecive cox-2 inhibitors

Answer 24

Incrases risk of CV events