Inflammatory Signaling Lab
PARK, Geunsoo
2010.4.14

 Introduction
1. Why we must study metastasis?
2. What is metastasis?
 Main Subject
3. AKT signal pathway
4. EMT
5. Aniokis Resistance
6. AKT regulation
 Conclusion
7. Therapy of PI3K/AKT pathway
8. Summary
9. Reference

 21.6% Cancer Death in whole death
 Cancer is most high in death statistic
 Cancer patients die 90% by metastasis

Nat Rev Cancer. 2007 Feb;7(2):79-94
 Malignant cells spread from the tumor of origin to colonize distant ogran.
 Metastasis steps consist of local invasion , intravasation, circulation, extravasation and colonization .

Nat Rev Drug Discov. 2005 Dec;4(12):988-1004

Nat Rev Cancer. 2009 Apr;9(4):265-73
EMT signaling networks
 Hyper-AKT decrease cell-cell connection by phosphorylation GSK-3β.
 Loss of E-cadherin through DNA methylation.
 Connection from AKT to
SNAIL induces EMT through decreasing cellcell adhesion.

Oncogene. 2007 Nov 22;26(53):7445-56

A.
The EGFR-mediated activation of
ERK and PI3K/AKT signaling leads to degradation of the Bim and inhibition of the apoptotic process.
B. Cell lacking contact with ECM fails to activate the prosurvival pathway.
C.
In metastasis cancer cells, always
ROS maintained high level. Cell lacking contact with ECM leads to degradation of the Bim and inhibition of the apoptotic process.
Antioxid Redox Signal. 2009 Nov;11(11):2791-806

AKT activation
 erbB/HER regulate cell growth and proliferation.
 EGF-I is involved in malignant transfrmation, tumor growth, local invasion and distant metastasis and Resistance to treatment.
 HGF is associated with cancer cell invasion.
 SFK are associated EMT, increased invasineness and malignant transformation.

▶
PI3K catalyses the conversion of PIP2 to PIP3.
▶
Two Phosphorylation
①
PDK1 at Thr-308 on the activation loop
② mTORC2 at Ser-473 on the hydrophobic motif

 PTEN directly antagonizes the activity of
PI3K by dephosphorylating phosphoinositides. (PIP3 → PIP2)
 PHLPP expression induced dephosphorylation AKT at Ser-473
 PP2A dephoshorylates Thr-308 of AKT on the activation loop and Modulates ERK activity.

Nat Rev Drug Discov. 2005 Dec;4(12):988-1004
Therapy target : PI3K inhibitor, AKT, mTOR, Other Pathway components.

Her2/Neu
↓
PI3K activation
↓
PIP2 → PIP3
↓ pAKT ← AKT
↓
GSK-3
β suppress
↓
SNAIL
↓
E-cadherin reduce
↓
Cell-cell Adhesion suppress
↓
EMT induce

 PI3K catalyzed phosphorylation of AKT on Ser-473.
 Activated AKT phosphorylates GSK-3β, causing its proteosomal removal.
 GSK-3β increases the negative transcription factor SNAIL.
 SNAIL decreases E-cadherin that forms adhesions between adjacent cells.
 Lowered E-cadherin can indirectly activate AKT.

• Metastasis and AKT activation. J Cell Physiol. 2009 Mar;218(3):451-4.
• Transitions between epithelial and mesenchymal states: acquisition of malignant
and stem cell traits. Nat Rev Cancer. 2009 Apr;9(4):265-73
• G-protein-coupled receptors and cancer. Nat Rev Cancer. 2007 Feb;7(2):79-94.
• Exploiting the PI3K/AKT pathway for cancer drug discovery Nat Rev Drug Discov.
2005 Dec;4(12):988-1004.
• Activation of NF-kappaB by Akt upregulates Snail expression and induces
epithelium mesenchyme transition Oncogene. 2007 Nov 22;26(53):7445-56. Epub
2007 Jun 11.
• Redox-based escape mechanism from death: the cancer lesson Antioxid Redox
Signal. 2009 Nov;11(11):2791-806.
• Molecular Medicine: Cancer, Signal Transduction, and the ras oncogenes (Chapter
13 Pathways of Intracellular Signal Transduction)