Serum bioactive lysophospholipids prevent TRAIL-induced apoptosis via PI3K/Akt-dependent cFLIP expression and Bad phosphorylation

Y. C. Kang, K. M. Kim, K. S. Lee, S. Namkoong, S. J. Lee, J. A. Han, D. Jeoung, K. S. Ha, Y. G. Kwon, Y. M. Kim

Research output: Contribution to journalArticlepeer-review

64 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1287-1298
Number of pages12
JournalCell Death and Differentiation
Volume11
Issue number12
DOIs
Publication statusPublished - 2004 Dec

Bibliographical note

Funding Information:
This work was supported by Vascular System Research Center grant from Korea Science and Engineering Foundation. We thank Dr. Peter K Kim (University of Pittsburgh) and Mrs. Elaine Por for helpful comments and critical reading of the manuscript.

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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