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

Seon Young Nam, Gyung Ah Jung, Gwong Cheung Hur, Hee Yong Chung, Woo Ho Kim, Dai Wu Seol, Byung Lan Lee

Research output: Contribution to journalArticle

113 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1066-1073
Number of pages8
JournalCancer Science
Volume94
Issue number12
DOIs
StatePublished - 1 Dec 2003

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CASP8 and FADD-Like Apoptosis Regulating Protein
Stomach Neoplasms
Up-Regulation
Apoptosis
Cell Line
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
TNF-Related Apoptosis-Inducing Ligand Receptors
Cycloheximide
Phosphatidylinositol 3-Kinase
Protein Synthesis Inhibitors
Caspase 8
RNA Stability
Retroviridae
Human Activities
Cell Survival
Tumor Necrosis Factor-alpha
Ligands
Infection

Cite this

Nam, Seon Young ; Jung, Gyung Ah ; Hur, Gwong Cheung ; Chung, Hee Yong ; Kim, Woo Ho ; Seol, Dai Wu ; Lee, Byung Lan. / Upregulation of FLIPs by Akt, a possible inhibition mechanism of TRAIL-induced apoptosis in human gastric cancers. In: Cancer Science. 2003 ; Vol. 94, No. 12. pp. 1066-1073.
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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.",
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Upregulation of FLIPs by Akt, a possible inhibition mechanism of TRAIL-induced apoptosis in human gastric cancers. / Nam, Seon Young; Jung, Gyung Ah; Hur, Gwong Cheung; Chung, Hee Yong; Kim, Woo Ho; Seol, Dai Wu; Lee, Byung Lan.

In: Cancer Science, Vol. 94, No. 12, 01.12.2003, p. 1066-1073.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Upregulation of FLIPs by Akt, a possible inhibition mechanism of TRAIL-induced apoptosis in human gastric cancers

AU - Nam, Seon Young

AU - Jung, Gyung Ah

AU - Hur, Gwong Cheung

AU - Chung, Hee Yong

AU - Kim, Woo Ho

AU - Seol, Dai Wu

AU - Lee, Byung Lan

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N2 - 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.

AB - 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.

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