Metastasis and AKT activation

Inflammatory Signaling LabPARK, Geunsoo

2010.4.14

Content

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

1. Why we must study metastasis?

21.6% Cancer Death in whole death

Cancer is most high in death statistic

Cancer patients die 90% by metastasis

2. What is the 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.

3. AKT signal pathway

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

4. EMT

EMT signaling networks

Hyper-AKT decrease cell-cell connection by phosphorylation GSK-3β.

Loss of E-cadherin through DNA methyla-tion.

Connection from AKT to SNAIL induces EMT through decreasing cell-cell adhesion.

Nat Rev Cancer. 2009 Apr;9(4):265-73

Cell morphology

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

5. Aniokis Resistance

Antioxid Redox Signal. 2009 Nov;11(11):2791-806

A. The EGFR-mediated activation of ERK and PI3K/AKT signaling leads to degradation of the Bim and inhibi-tion 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 lack-ing contact with ECM leads to degradation of the Bim and inhibi-tion of the apoptotic process.

6. AKT Regulation

AKT activation

erbB/HER regulate cell growth and proliferation.

EGF-I is involved in malignant transfrmation, tumor growth, local invasion and dis-tant metastasis and Resistance to treatment.

HGF is associated with cancer cell invasion.

SFK are associated EMT, increased invasineness and malignant transformation.

AKT Activation

▶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

AKT Inhibition

PTEN directly antagonizes the activity of PI3K by dephosphorylating phosphoinosi-tides. (PIP3 → PIP2)

PHLPP expression induced dephosphoryla-tion AKT at Ser-473

PP2A dephoshorylates Thr-308 of AKT on the activation loop and Modulates ERK ac-tivity.

7. Therapy though PI3K/AKT pathway

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

Therapy target : PI3K inhibitor, AKT, mTOR, Other Pathway components.

8. Summary

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

8. Summary

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.

9. Reference

• 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 epithe-

lium 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 Si-gnal. 2009 Nov;11(11):2791-806.

• Molecular Medicine: Cancer, Signal Transduction, and the ras oncogenes (Chapter 13 Pathways of Intracellular Signal Transduction)