Autotaxin stimulates urokinase-type plasminogen activator expression through phosphoinositide 3-kinase-Akt-nuclear [corrected] factor kappa B signaling cascade in human melanoma cells.
Autotaxin, a lysophospholipase D producing lysophosphatidic acid, augments invasive and metastatic potential of tumor cells. Current investigations have focused on understanding the molecular mechanisms by which autotaxin regulates the expression of a major mediator of tumor invasion and metastasis, urokinase-type plasminogen activator (uPA) in human A2058 melanoma cells. Autotaxin induced uPA expression in a dose-dependent manner that was inhibited by pharmacological inhibitors for Gi (pertussis toxin), phosphoinositide 3-kinase (PI3K, LY294002), Akt inhibitor (AktI), proteosome activity and IkappaB phosphorylation (pyrrolidine dithiocarbamate), and by a dominant negative mutant (DN) of Akt. Autotaxin phosphorylated Akt and induced the translocation of nuclear [corrected] factor-kappaB (NF-kappaB) to the nucleus that were inhibited by AktI or by overexpressing DN-Akt. Consistently, green fluorescence protein-tagged p65 of NF-kappaB accumulated in the nucleus by autotaxin that was abrogated when the cells were transfected with DN-Akt. Moreover, autotaxin increased the DNA binding ability of NF-kappaB and promoter activity of uPA. Collectively, these data strongly suggest autotaxin induces uPA expression via the Gi-PI3K-Akt-NF-kappaB signaling pathway that might be critical for autotaxin-induced tumor cell invasion and metastasis.
Lee
Jangsoon
J
College of Medicine, Konyang University, Daejeon, Korea.
Duk Jung
In
I
Gyo Park
Chang
C
Han
Jeung-Whan
JW
Young Lee
Hoi
H
D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D008545:Melanoma / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D009097:Multienzyme Complexes / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D043264:Phosphodiesterase I / Q000502:physiology*; D010727:Phosphoric Diester Hydrolases; D010766:Phosphorylation; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011755:Pyrophosphatases / Q000502:physiology*; D011994:Recombinant Proteins / Q000737:chemistry; D015398:Signal Transduction; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis*; D000099189:Lysophospholipase D
D009097:Multienzyme Complexes; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases; D051057:Proto-Oncogene Proteins c-akt; D011755:Pyrophosphatases; D011994:Recombinant Proteins; D014568:Urokinase-Type Plasminogen Activator; D000099189:Lysophospholipase D