Inhibition of autotaxin production or activity blocks lysophosphatidylcholine-induced migration of human breast cancer and melanoma cells.
Increased expression of autotaxin in tumors including glioblastoma, breast, renal, ovarian, lung, and thyroid cancers is associated with increased tumor aggressiveness. Autotaxin promotes metastasis as well as cell growth, survival, and migration of cancer cells. These actions could depend on the noncatalytic effects of autotaxin on cell adhesion, or the catalytic activity of autotaxin, which converts lysophosphatidylcholine into lysophosphatidate in the extracellular fluid surrounding the tumor. Both lysophosphatidylcholine (LPC) and lysophosphatidate have been reported to stimulate migration through their respective G-protein coupled receptors. The present study determines the roles of autotaxin, LPC, and lysophosphatidate in controlling the migration of two cancer cell lines: MDA-MB-231 breast cancer cells, which produce little autotaxin and MDA-MB-435 melanoma cells that secrete significant levels of autotaxin. LPC alone was unable to stimulate the migration of either cell type unless autotaxin was present. Knocking down autotaxin secretion, or inhibiting its catalytic activity, blocked cell migration by preventing lysophosphatidate production and the subsequent activation of LPA(1/3) receptors. We conclude that inhibiting autotaxin production or activity could provide a beneficial adjuvant to chemotherapy for preventing tumor growth and metastasis in patients with high autotaxin expression in their tumors.
Gaetano
Cristoforo G
CG
Department of Biochemistry, Signal Transduction Research Group, University of Alberta, Edmonton, Alberta, Canada T6G 2S2.
Samadi
Nasser
N
Tomsig
Jose L
JL
Macdonald
Timothy L
TL
Lynch
Kevin R
KR
Brindley
David N
DN
D000813:Anilides / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002384:Catalysis / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008244:Lysophosphatidylcholines / Q000378:metabolism / Q000494:pharmacology*; D008246:Lysophospholipids / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010755:Organophosphates / Q000494:pharmacology; D063065:Organophosphonates / Q000494:pharmacology; D043264:Phosphodiesterase I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases; D011725:Pyridines / Q000494:pharmacology; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D000099189:Lysophospholipase D
D000813:Anilides; D004791:Enzyme Inhibitors; D008244:Lysophosphatidylcholines; D008246:Lysophospholipids; D009097:Multienzyme Complexes; D010755:Organophosphates; D063065:Organophosphonates; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases; D011725:Pyridines; D011755:Pyrophosphatases; D034741:RNA, Small Interfering; D049368:Receptors, Lysophosphatidic Acid; D000099189:Lysophospholipase D; C533861:(4-(tetradecanoylamino)benzyl)phosphonic acid; C529824:VPC32183; C032881:lysophosphatidic acid