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

• Published in: Cell death and differentiation Vol. 11; no. 12; pp. 1287 - 1298
• Main 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
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.12.2004
• Subjects: Acids; Adult; Animals; Apoptosis; Apoptosis - physiology; Apoptosis Regulatory Proteins; bcl-Associated Death Protein; Biochemistry; Carrier Proteins - metabolism; CASP8 and FADD-Like Apoptosis Regulating Protein; Caspases - drug effects; Caspases - metabolism; Cattle; Cell death; Cell Line, Tumor; Clone Cells; Cytochrome; Cytokines; Down-Regulation - drug effects; Down-Regulation - physiology; Drug Resistance, Neoplasm - physiology; Female; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; Ligands; Lysophospholipids - blood; Lysophospholipids - pharmacology; Male; Membrane Glycoproteins - metabolism; Membrane Glycoproteins - pharmacology; Middle Aged; Ovarian Neoplasms - blood; Ovarian Neoplasms - immunology; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Phosphorylation - drug effects; Protein Transport - drug effects; Protein Transport - physiology; Protein-Serine-Threonine Kinases - metabolism; Proteins; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Signal transduction; Signal Transduction - drug effects; Signal Transduction - physiology; Sphingosine - analogs & derivatives; Sphingosine - blood; Sphingosine - pharmacology; TNF-Related Apoptosis-Inducing Ligand; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - pharmacology; Tumor necrosis factor-TNF; Up-Regulation - drug effects; Up-Regulation - physiology
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/sj.cdd.4401489

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.