Decoy receptor 3 expression in AsPC-1 human pancreatic adenocarcinoma cells via the phosphatidylinositol 3-kinase-, Akt-, and NF-κB-dependent pathway
Journal
Journal of Immunology
Journal Volume
181
Journal Issue
12
Pages
8441-8449
Date Issued
2008
Author(s)
Chen P.-H.
Abstract
Many cancers develop different means of escaping destruction by the immune system, such as resistance to Fas ligand (FasL)-Fas interaction-mediated apoptotic signals. Decoy receptor 3 (DcR3), a soluble receptor for FasL, is highly expressed in cancer cells and plays a significant role in immune suppression and tumor progression. However, how DcR3 expression is modulated is unclear. In this study, immunoprecipitation and ELISA using human pancreatic cancer cells showed the presence of high levels of DcR3 protein in AsPC-1 cells, but not in PANC-1 cells. Treatment with herbimycin A (a tyrosine kinase inhibitor), LY294002 or wortmannin (PI3K inhibitors), pyrrolidine dithiocarbamate (an NF-κB inhibitor), or AG1024 (an insulin-like growth factor-1 inhibitor) significantly reduced endogenous DcR3 levels in AsPC-1 cells. Furthermore, transfection of AsPC-1 cells with Akt or IκBα dominant-negative plasmids also markedly reduced DcR3 levels. In contrast, 48-h transfection of PANC-1 cells with a constitutively active Akt induced DcR3 expression. Flow cytometry assays indicated that apoptosis was not seen in AsPC-1 cells incubated with soluble FasL or membrane-bound FasL, but was seen when DcR3 small interfering RNA-transfected AsPC-1 cells underwent the same treatment. In addition, PANC-1 cell incubation with conditioned medium from AsPC-1 cells transfected with dominant-negative Akt or IκBα plasmids or DcR3 small interfering RNA showed increased soluble FasL-mediated apoptosis compared with the control group. Our results show that insulin-like growth factor-1-induced activation of the PI3K/Akt/NF-κB signaling pathway is involved in the modulation of endogenous DcR3 expression in AsPC-1 cells, and that reducing endogenous DcR3 levels increases FasL-induced apoptosis of human pancreatic cancer cells. Copyright ? 2008 by The American Association of Immunologists, Inc.
SDGs
Other Subjects
2 morpholino 8 phenylchromone; 3 bromo 5 tert butyl 4 hydroxybenzylidenemalononitrile; decoy receptor 3; Fas ligand; herbimycin A; immunoglobulin enhancer binding protein; phosphatidylinositol 3 kinase; protein kinase B; pyrrolidine dithiocarbamate; small interfering RNA; somatomedin C; wortmannin; CHUK protein, human; decoy receptor 3; Fas ligand; FASLG protein, human; I kappa B kinase; IKBKB protein, human; phosphatidylinositol 3 kinase; protein kinase B; unclassified drug; apoptosis; article; cancer cell culture; controlled study; human; human cell; nucleotide sequence; pancreas adenocarcinoma; priority journal; protein expression; signal transduction; tumor escape; adenocarcinoma; biosynthesis; carcinoma; cell strain HT29; drug antagonism; enzymology; genetics; immunology; leukemia cell line; metabolism; pancreas tumor; pathology; physiology; signal transduction; tumor cell line; 1-Phosphatidylinositol 3-Kinase; Adenocarcinoma; Apoptosis; Carcinoma; Cell Line, Tumor; Fas Ligand Protein; HT29 Cells; Humans; I-kappa B Kinase; Jurkat Cells; Pancreatic Neoplasms; Proto-Oncogene Proteins c-akt; Receptors, Tumor Necrosis Factor, Member 6b; RNA, Small Interfering; Signal Transduction
Type
journal article