Inhibition of Akt/PKB by a COX-2 inhibitor induces apoptosis in gastric cancer cells.

Abstract

BACKGROUND/AIM:

Inhibition of cyclooxygenase-2 has been proposed to be a potential mechanism for the chemoprevention of gastrointestinal tumors by nonsteroidal anti-inflammatory drugs. This study investigates the mechanisms by which the cyclooxygenase-2 inhibitor SC236 induces apoptosis of gastric cancer cell lines and its downstream signaling pathway.

METHODS:

Two gastric cancer cell lines, AGS and MKN28, were treated with SC236 and assessed for cell growth and apoptosis. The involvement of mitogen-activated protein kinase and Akt kinase/protein kinase B (Akt/PKB) pathways and their downstream signalings were studied in the AGS cell line.

RESULTS:

SC236 treatment induced apoptosis in gastric cancer cells and caused activation of p38 and stress-activated protein kinase/jun kinase, but down-regulated Akt/PKB. The specific p38 inhibitor SB203580 and the dominant-negative stress-activated protein kinase/jun kinase both failed, while the constitutively active form of Akt/PKB was able to block SC236-induced apoptosis. SC236-induced apoptosis was coupled with release of cytochrome c and activation of caspases.

CONCLUSION:

One of the pathways involved in SC-236-induced apoptosis in gastric cancer cells is through downregulation of Akt and then release of cytochrome c.

• Authors: Xiao Ming Fan, Xiao Hua Jiang, Qing Gu, Yick Pang Ching, Hua He, Harry H X Xia, Marie Chia Mi Lin, Annie O O Chan, Man Fung Yuen, Hsiang-Fu Kung, Benjamin Chun-Yu Wong
• Journal: Digestion (Digestion) Vol. 73 Issue 2-3 Pg. 75-83 ( 2006) ISSN: 0012-2823 [Print] Switzerland
• PMID: 16641552 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2006 S. Karger AG, Basel.

Chemical References

• 4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide
• Cyclooxygenase 2 Inhibitors
• Pyrazoles
• Sulfonamides
• Cytochromes c
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinases
• Caspases
• Acridine Orange

Topics

• Acridine Orange
• Adenocarcinoma (pathology)
• Apoptosis (drug effects)
• Blotting, Western
• Caspases (metabolism)
• Cyclooxygenase 2 Inhibitors (pharmacology)
• Cytochromes c (metabolism)
• Down-Regulation
• Enzyme Activation
• Humans
• Mitogen-Activated Protein Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors)
• Pyrazoles (pharmacology)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction
• Stomach Neoplasms (pathology)
• Sulfonamides (pharmacology)
• Transfection
• Tumor Cells, Cultured