Autotaxin protects MCF-7 breast cancer and MDA-MB-435 melanoma cells against Taxol-induced apoptosis.
Autotaxin (ATX) promotes cancer cell survival, growth, migration, invasion and metastasis. ATX converts extracellular lysophosphatidylcholine (LPC) into lysophosphatidate (LPA). As these lipids have been reported to affect cell signaling through their own G-protein-coupled receptors, ATX could modify the balance of this signaling. Also, ATX affects cell adhesion independently of its catalytic activity. We investigated the interactions of ATX, LPC and LPA on the apoptotic effects of Taxol, which is commonly used in breast cancer treatment. LPC had no significant effect on Taxol-induced apoptosis in MCF-7 breast cancer cells, which do not secrete significant ATX. Addition of incubation medium from MDA-MB-435 melanoma cells, which secrete ATX, or recombinat ATX enabled LPC to inhibit Taxol-induced apoptosis of MCF-7 cells. Inhibiting ATX activity blocked this protection against apoptosis. We conclude that LPC has no significant effect in protecting MCF-7 cells against Taxol treatment unless it is converted to LPA by ATX. LPA strongly antagonized Taxol-induced apoptosis through stimulating phosphatidylinositol 3-kinase and inhibiting ceramide formation. LPA also partially reversed the Taxol-induced arrest in the G2/M phase of the cell cycle. Our results support the hypothesis that therapeutic inhibition of ATX activity could improve the efficacy of Taxol as a chemotherapeutic agent for cancer treatment.
Samadi
N
N
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
Gaetano
C
C
Goping
I S
IS
Brindley
D N
DN
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002518:Ceramides / Q000378:metabolism; D006801:Humans; D008244:Lysophosphatidylcholines / Q000378:metabolism; D008246:Lysophospholipids / Q000502:physiology; D008545:Melanoma / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009097:Multienzyme Complexes / Q000502:physiology*; D017239:Paclitaxel / Q000494:pharmacology*; D043264:Phosphodiesterase I / Q000502:physiology*; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000099189:Lysophospholipase D
D002518:Ceramides; D008244:Lysophosphatidylcholines; D008246:Lysophospholipids; D009097:Multienzyme Complexes; D017239:Paclitaxel; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D012333:RNA, Messenger; D000099189:Lysophospholipase D; C032881:lysophosphatidic acid