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- Title
Serum bioactive lysophospholipids prevent TRAIL-induced apoptosis via PI3K/Akt-dependent cFLIP expression and Bad phosphorylation.
- Authors
Kang, Y.-C.; Kim, K.-M.; Lee, K.-S.; Namkoong, S.; Lee, S.-J.; Han, J.-A.; Jeoung, D.; Ha, K.-S.; Kwon, Y.-G.; Kim, Y.-M.
- Abstract
Serum contains a variety of biomolecules, which play an important role in cell proliferation and survival. We sought to identify the serum factor responsible for mitigating tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis and to investigate its molecular mechanism. TRAIL induced effective apoptosis without serum, whereas bovine serum decreased apoptosis by suppressing cytochrome c release and caspase activation. Indeed, albumin-bound lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) inhibited TRAIL-induced apoptosis by suppressing caspase activation and cytochrome c release. LPA increased phosphatidylinositol 3-kinase (PI3K)-dependent Akt activation, cellular FLICE-inhibitory protein (cFLIP) expression, and Bad phosphorylation, resulting in inhibition of caspase-8 activation and Bad translocation to mitochondria. The antiapoptotic effect of LPA was abrogated by PI3K inhibitor, transfection with dominant-negative Akt, and specific downregulation of cFLIP expression using siRNA and further increased by siRNA-mediated suppression of Bad expression. Moreover, sera from ovarian cancer patients showed more protective effect against TRAIL-induced apoptosis than those from healthy donors, and this protection was suppressed by PI3K inhibitor. Our results indicate that albumin-bound LPA and S1P prevent TRAIL-induced apoptosis by upregulation of cFLIP expression and in part by Bad phosphorylation, through the activation of PI3K/Akt pathway.Cell Death and Differentiation (2004) 11, 1287-1298. doi:10.1038/sj.cdd.4401489 Published online 6 August 2004
- Subjects
SERUM; BLOOD plasma; CELL proliferation; CELL cycle; APOPTOSIS; LIGANDS (Biochemistry)
- Publication
Cell Death & Differentiation, 2004, Vol 11, Issue 12, p1287
- ISSN
1350-9047
- Publication type
Article
- DOI
10.1038/sj.cdd.4401489