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  • Original Paper
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Low glucose-enhanced TRAIL cytotoxicity is mediated through the ceramide–Akt–FLIP pathway

Abstract

To examine whether the tumor microenvironment alters cytokine-induced cytotoxicity, human prostate adenocarcinoma DU-145 cells were exposed to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and/or glucose deprivation, a common characteristic of the tumor microenvironment. TRAIL alone reduced cell survival in a dose-dependent manner. Glucose deprivation alone induced no cytotoxicity within 4 h. However, the combination of TRAIL (50 ng/ml) and glucose deprivation for 4 h increased cell death and PARP cleavage by promoting activation of caspase-8 and caspase-3, relative to that of TRAIL alone. Similar results were observed in human colorectal carcinoma CX-1 cells. Data from immunoblotting analysis reveal that glucose deprivation-enhanced TRAIL cytotoxicity is inversely related to the intracellular level of FLICE inhibitory protein (FLIP) but not that of death receptor 5 (DR5). Results from mass spectrometry show that glucose deprivation elevates ceramide. The elevation of ceramide may cause dephosphorylation of Akt and maintain dephosphorylation of Akt in the presence of TRAIL and then subsequently down-regulate the expression of FLIP. Taken together, the present studies suggest that glucose deprivation enhances TRAIL-induced cytotoxicity through the ceramide–Akt–FLIP pathway.

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Abbreviations

AMPK:

AMP-activated protein kinase

CAPP:

ceramide-activated protein phosphatase

DcR1:

decoy receptor 1

DcR2:

decoy receptor 2

DR4:

death receptor 4

DR5:

death receptor 5

FADD:

Fas-associated death domain

FasL:

Fas ligand

FLICE:

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

FLIP:

FLICE inhibitory protein

GSH:

glutathione

NAC:

N-acetyl-L-cysteine

PAGE:

polyacrylamide gel electrophoresis

PARP:

poly (ADP-ribose) polymerase

PBS:

phosphate-buffered saline

PI(3)K:

phosphatidylinositol-3-kinase

PP1:

protein phosphatase-1

PP2A:

2A class of Ser/Thr protein phosphatase

SDS:

sodium dodecyl sulfate

SMase:

sphingomyelinase

SNP:

sodium nitroprusside

TNF:

tumor necrosis factor

TRAIL:

tumor necrosis factor-related apoptosis-inducing ligand

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This work was supported by NCI grant CA48000 and Elsa U Pardee Foundation.

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Correspondence to Yong J Lee.

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Nam, S., Amoscato, A. & Lee, Y. Low glucose-enhanced TRAIL cytotoxicity is mediated through the ceramide–Akt–FLIP pathway. Oncogene 21, 337–346 (2002). https://doi.org/10.1038/sj.onc.1205068

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