title: Lysophosphatidic Acid Triggers Apoptosis in HeLa Cells through the Upregulation of Tumor Necrosis Factor Receptor Superfamily Member 21.
abstract: Lysophosphatidic acid (LPA), a naturally occurring bioactive phospholipid, activates G protein-coupled receptors (GPCRs), leading to regulation of diverse cellular events including cell survival and apoptosis. Despite extensive studies of the signaling pathways that mediate LPA-regulated cell growth and survival, the mechanisms underlying the apoptotic effect of LPA remain largely unclear. In this study, we investigated this issue in HeLa cells. Our data demonstrate that LPA induces apoptosis in HeLa cells at pathologic concentrations with a concomitant upregulation of the expression of TNFRSF21 (tumor necrosis factor receptor superfamily member 21), also known as death receptor number 6 (DR6) involved in inflammation. Moreover, treatment of cells with LPA receptor (LPAR) antagonist abolished the DR6 upregulation by LPA. LPA-induced DR6 expression was also abrogated by pertussis toxin (PTX), an inhibitor of GPCRs, and by inhibitors of PI3K, PKC, MEK, and ERK. Intriguingly, LPA-induced DR6 expression was specifically blocked by dominant-negative form of PKCδ(PKCδ-DN). LPA-induced DR6 expression was also dramatically inhibited by knockdown of ERK or CREB. These results suggest that activation of the MEK/ERK pathway and the transcription factor CREB mediate LPA-induced DR6 expression. More interestingly, knockdown of DR6 using siRNA approach remarkably attenuated LPA-induced apoptosis. In conclusion, our results suggest that LPA-induced apoptosis in HeLa cells is mediated by the upregulation of DR6 expression.
authors.affiliation: Department of Biomedical & Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996, USA; Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Yunzhou
authors.identifier: 0000-0003-2474-957X
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA; David Geffen UCLA School of Medicine and UCLA Jonson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095, USA.
authors.forename: Yong
authors.identifier: 0000-0002-1698-0897
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Biomedical & Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996, USA.
authors.forename: Mei-Zhen
authors.identifier: 0000-0003-4745-6999
authors.initials: MZ
authors.lastname: Cui
authors.affiliation: Department of Biomedical & Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996, USA.
authors.forename: Xuemin
authors.identifier: 0000-0002-7426-272X
authors.initials: X
authors.lastname: Xu
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015152:Blotting, Northern; D015153:Blotting, Western; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D020287:In Situ Nick-End Labeling; D008246:Lysophospholipids / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D037342:Pertussis Toxin / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering / Q000235:genetics / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D048049:Extracellular Signal-Regulated MAP Kinases; D008246:Lysophospholipids; D037342:Pertussis Toxin; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering; D018124:Receptors, Tumor Necrosis Factor; C115163:CREB1 protein, human; C114109:TNFRSF21 protein, human; C032881:lysophosphatidic acid