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Slide 1 Hello, my name is Ji-young Lim, and I’m
graduate student of bio and brain engineering. Today’s lecture topic is about an anti-cancer
strategy by modulating the cancer cell signaling.
Slide 2 We looked upon the basic knowledge last time,
now this lecture is about the new role of ROS.
ROS is basically very harmful, but it is revealed that it also acts as signaling molecule.
This new concept is proposed recently around nineteen-ninety-four.
Slide 3 So, today, we will focus on Professor Kang’s
2 research articles. One is on the Nature at 2005, and the other
one is on the Molecular Cell at two-thousand-eleven. They both focus on peroxiredoxin, an antioxidant
enzyme, for regulation of cell signaling pathways.
Slide 4 So, peroxiredoxin is one of the type of the
antioxidant enzymes. There are 4 types of antioxidant enzymes and
only peroxiredoxin works in the signaling cascade.
Slide 5 And you should know about two cell membrane
receptors, PDGFR and VEGFR for this lecture. PDGFR is a receptor for PDGF, platelet-derived
growth factor. VEGFR is a receptor for VEGF, vascular endothelial growth factor.
They work for cell growth and angiogenesis. And they are both receptor tyrosine kinases.
Slide 6 Let’s see how receptor tyrosine kinase works.
Receptor tyrosine kinase is, by its name, a receptor which phosphorylates tyrosine sites
of protein. Once the signal molecule binds to it, it forms
dimer and they phosphorylate each other and become an active form. So if we get rid of
phosphates, it becomes an inactive form.
Slide 7 So let’s find the role of peroxiredoxin
and hydrogen peroxide in PDGF signaling. First, they deleted prx2 from mouse embryonic
fibroblast, (MEF), and H2O2 level went up and PDGFR was activated.
Thus, we can say that, normally, prx2 is repressing PDGFR activity, so it is a negative regulator
of PDGF signaling.
Slide 8 The next question is, how did this happen?
By Prx2 itself, or by hydrogen peroxide? Co-immunoprecipitation result showed that
Prx2 and PDGFR are co-localized in the cell. Thus it means hydrogen peroxide near the PDGFR
were removed by prx2 and it impaired PDGFR. So they made a model for this: oxidative inactivation
of protein tyrosine phosphatases.
Slide 9 Let’s see how this model works. You should
follow very well to understand in here. When there is prx2, it goes to PDGFR and removes
surrounding H2O2. Now PTPase is in its active form and it removes
phosphate from PDGFR. So PDGFR is inactivated. If we remove Prx2, exactly opposite things
happen. Now PDGFR is activated.
Slide 10 We saw PDGFR regulation before. It worked
with PTPase oxidation. Now we will look upon the other mechanism.
Prx2 acts in opposite ways in PDGFR and VEGFR. In VEGFR, H2O2 directly inhibits VEGFR by
oxidizing active site. No PTPase in here. Thus, we can say that Prx2 is protecting the
VEGFR from oxidization. And the interesting thing in here is they
make caveolae structure. Without this, Prx cannot work properly. They are closely located
together and Prx2 protects VEGFR from oxidation in caveolae structure.
Slide 11 You can see caveolae structure image and VEGFR
and Prx2 in it. And they showed tumor regression in prx2 deficiency.
Because Prx2 was protecting VEGFR from oxidation, removing prx2 resulted in oxidation of VEGFR,
inactivation of it, thus inactivated angiogenesis and it made tumor regression.
Slide 12 If we summarize this all together, the important
thing in here is that ROS regulates PDGFR and VEGFR in opposite way. For PDGFR,
they impairs PTPase first, so they activate PDGFR. But for VEGFR, they directly oxidizes
them, so they inactivates VEGFR.
Slide 13 Let’s summarize what we have discussed until
now. • ROS have role as signal molecule!
• Thus we can expect tumor regulation with antioxidant enzyme
• Maybe this can be the next paradigm for cancer treatment
Thank you for listening. ^^