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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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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DOI: https://doi.org/10.1038/sj.onc.1205068
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