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


CONCLUSIONS
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.
Fan
Xiao Ming
XM
Department of Medicine, Jinshan Hospital of the Fudan University, Shanghai, China.
Jiang
Xiao Hua
XH
Gu
Qing
Q
Ching
Yick Pang
YP
He
Hua
H
Xia
Harry H X
HH
Lin
Marie Chia Mi
MC
Chan
Annie O O
AO
Yuen
Man Fung
MF
Kung
Hsiang-Fu
HF
Wong
Benjamin Chun-Yu
BC
D000165:Acridine Orange; D000230:Adenocarcinoma / Q000473:pathology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000473:pathology*; D013449:Sulfonamides / Q000494:pharmacology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D000096926:Benzenesulfonamides
D000165:Acridine Orange; D020169:Caspases; D052246:Cyclooxygenase 2 Inhibitors; D045304:Cytochromes c; D020928:Mitogen-Activated Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D011720:Pyrazoles; D013449:Sulfonamides; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides