1 / 15

Metastasis and AKT activation

Metastasis and AKT activation. Inflammatory Signaling Lab PARK, 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

irving
Download Presentation

Metastasis and AKT activation

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Metastasis and AKT activation Inflammatory Signaling Lab PARK, Geunsoo 2010.4.14

  2. 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

  3. 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

  4. 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, extravasationand colonization.

  5. 3. AKT signal pathway Nat Rev Drug Discov. 2005 Dec;4(12):988-1004

  6. 4. EMT • 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 cell-cell adhesion. Nat Rev Cancer. 2009 Apr;9(4):265-73 EMT signaling networks

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

  8. 5. Aniokis Resistance The EGFR-mediated activation of ERK and PI3K/AKT signaling leads to degradation of the Bim and inhibition of the apoptotic process. Cell lacking contact with ECM fails to activate the prosurvival pathway. 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

  9. 6. AKT Regulation 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.

  10. 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

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

  12. 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.

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

  14. 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.

  15. 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 Aktupregulates 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 rasoncogenes(Chapter 13 Pathways of Intracellular Signal Transduction)

More Related