Serum bioactive lysophospholipids prevent TRAIL-induced apoptosis via PI3K/Akt-dependent cFLIP expression and Bad phosphorylation.
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.
Department of Molecular and Cellular Biochemistry, College of Medicine, Kangwon National University, Chunchon, Kangwon-Do 200-701, Korea.
Y-C
YC
Kang
K-M
KM
Kim
K-S
KS
Lee
S
S
Namkoong
S-J
SJ
Lee
J-A
JA
Han
D
D
Jeoung
K-S
KS
Ha
Y-G
YG
Kwon
Y-M
YM
Kim
D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000378:metabolism*; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D045744:Cell Line, Tumor; D002999:Clone Cells; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008246:Lysophospholipids / Q000097:blood* / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism* / Q000494:pharmacology; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000097:blood* / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D051025:bcl-Associated Death Protein
D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins; D020169:Caspases; D047908:Intracellular Signaling Peptides and Proteins; D008246:Lysophospholipids; D008562:Membrane Glycoproteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D013110:Sphingosine; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; D051025:bcl-Associated Death Protein; C494819:BAD protein, human; C506386:CFLAR protein, human; C505653:TNFSF10 protein, human; C060506:sphingosine 1-phosphate; C494918:AKT1 protein, human; C032881:lysophosphatidic acid