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. 2005 Aug 19;94(12):1066–1073. doi: 10.1111/j.1349-7006.2003.tb01402.x

Upregulation of FLIPS by Akt, a possible inhibition mechanism of TRAIL‐induced apoptosis in human gastric cancers

Seon Young Nam 1,2, Gyung‐Ah Jung 1, Gwong‐Cheung Hur 1, Hee‐Yong Chung 3, Woo Ho Kim 2,4, Dai‐Wu Seol 5, Byung Lan Lee 1,✉
PMCID: PMC11160312  PMID: 14662022

Abstract

Tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) is a potent inducer of apoptosis in some, but not all cancer cells. To assess the regulation of TRAIL‐resistance in the human gastric cancer cells, we examined TRAIL sensitivity, TRAIL receptor expression, and intracellular signaling events induced by TRAIL. All the gastric cancer cell lines tested were susceptible to TRAIL to some extent except for SNU‐216 cell line, which was completely resistant. TRAIL receptor expression was not related to the TRAIL‐sensitivity. Of the cell lines tested, SNU‐216 showed the highest level of constitutively active Akt and the short form of FLICE inhibitory protein (FLIPS). Treatment with the phosphatidylinositol 3‐kinase (PI3K) inhibitor LY294002 or with the protein synthesis inhibitor cycloheximide induced a suppression of constitutive Akt activation in SNU‐216 cells and a concomitant decrease in the expression of FLIPS. The reduction of Akt activity by LY294002 affected the transcriptional level of FLIPS, but not the mRNA stability. As a result, LY294002 or cycloheximide significantly enhanced TRAIL‐induced apoptosis. Moreover, the overexpression of constitutively active Akt in the TRAIL‐sensitive cell line, SNU‐668, rendered the cell line resistant to TRAIL. In addition, infection of the same cell line with retrovirus expressing FLIPS completely inhibited TRAIL‐induced apoptosis by blocking the activation of caspase‐8. Therefore, our results suggest that Akt activity promotes human gastric cancer cell survival against TRAIL‐induced apoptosis via upregulation of FLIPS, and that the cytotoxic effect of TRAIL can be enhanced by modulating the Akt/FLIPS pathway in human gastric cancers.

The abbreviations used are:

DcR1

decoy receptor 1

DcR2

decoy receptor 2

DR4

death receptor 4

DR5

death receptor 5

EGFP

enchanced green fluorescent protein

FADD

Fas‐associated death domain

FasL

Fas ligand

FLICE

Fas‐associated death domain‐like interleukin‐1β‐converting enzyme

FLIP

FLICE inhibitory protein

MAPK

mitogen‐activated protein kinase

MKK

MAPK kinase

PAGE

polyacrylamide gel electrophoresis

PARP

poly(ADP‐ribose) polymerase

PI3K

phosphatidylinositol‐3 kinase

SDS

sodium dodecyl sulfate

TNF

tumor necrosis factor

TRAIL

tumor necrosis factor‐related apoptosis‐inducing ligand

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