Dual mechanisms for lysophospholipid induction of proliferation of human breast carcinoma cells.
Endothelial differentiation gene-encoded G protein-coupled receptors (Edg Rs) Edg-1, Edg-3, and Edg-5 bind sphingosine 1-phosphate (S1P), and Edg-2 and Edg-4 Rs bind lysophosphatidic acid (LPA). LPA and S1P initiate ras- and rho-dependent signaling of cellular growth. Cultured lines of human breast cancer cells (BCCs) express Edg-3 > Edg-4 > Edg-5 > or = Edg-2, without detectable Edg-1, by both assessment of mRNA and Western blots with rabbit and monoclonal mouse anti-Edg R antibodies. BCC proliferation was stimulated significantly by 10(-9) M to 10(-6) M LPA and S1P. Luciferase constructs containing the serum response element (SRE) of growth-related gene promoters reported mean activation of BCCs by LPA and S1P of up to 85-fold. LPA and S1P stimulated BCC secretion of type II insulin-like growth factor (IGF-II) by 2-7-fold, to levels at which exogenous IGF-II stimulated increased proliferation and SRE activation of BCCs. All BCC responses to LPA and S1P were suppressed similarly by pertussis toxin, mitogen-activated protein kinase kinase inhibitors, and C3 exoenzyme inactivation of rho, suggesting mediation by Edg Rs. Monoclonal anti-IGF-II and anti-IGFR1 antibodies suppressed proliferation and SRE reports of BCCs to LPA and S1P by means of up to 65%. Edg Rs thus transduce LPA and S1P enhancement of BCC growth, both directly through SRE and indirectly by enhancing the contribution of IGF-II.
Goetzl
E J
EJ
Department of Medicine, University of California Medical Center, San Francisco 94143-0711, USA. egoetzl@itsa.ucsf.edu
Dolezalova
H
H
Kong
Y
Y
Zeng
L
L
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001943:Breast Neoplasms; D002455:Cell Division / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins; D017874:Immediate-Early Proteins / Q000032:analysis / Q000235:genetics*; D008246:Lysophospholipids / Q000494:pharmacology*; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D011817:Rabbits; D011956:Receptors, Cell Surface / Q000032:analysis / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D049312:Receptors, Lysophospholipid; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000906:Antibodies; D000911:Antibodies, Monoclonal; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D017874:Immediate-Early Proteins; D008246:Lysophospholipids; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D049312:Receptors, Lysophospholipid; D014157:Transcription Factors; D000072000:NF-KappaB Inhibitor alpha; C060506:sphingosine 1-phosphate; D013110:Sphingosine