title: Alpha-fetoprotein contributes to THP-1 cell invasion and chemotaxis via protein kinase and Gi-protein-dependent pathways.
abstract: Alpha-fetoprotein (AFP) for long was known as immunomodulator and tumor marker having multifaceted actions on the activity of normal and transformed cells. In present study, we have investigated the involvement of AFP in regulation of THP-1 cell line invasion and underlying mechanisms. Treatment with human recombinant AFP causes up-regulation of MMP9 expression, chemotaxis and calcium mobilization, and increases invasion through Matrigel, with no significant impact on THP-1 cell growth or viability. Using small molecule inhibitors, we have shown that the rhAFP-induced MMP9 expression depends on the activation of ERK1,2, JNK and Akt kinases, with the involvement of NFκB and likely, AP-1 transcription factors. In contrast, inhibition of p38 kinase, but not of JNK, had dramatic suppressive effect on the rhAFP-triggered chemotaxis. In addition, rhAFP-induced MMP9 expression and calcium response were completely blocked by pertussis toxin, indicating that Gi-protein-coupled receptor(s) has a mediatory role in these processes. CCR5 chemokine receptor is the only known Gi-protein binding to AFP. The action of CCR5 inhibitor Maraviroc results in partial suppression of MMP9 up-regulation and calcium response suggesting that CCR5 might be involved in these effects.
authors.affiliation: Institute of Experimental Cardiology, Cardiology Research and Production Center, Moscow, Russia.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Zubkova
authors.forename: Lidiya
authors.initials: L
authors.lastname: Semenkova
authors.forename: Elena
authors.initials: E
authors.lastname: Dudich
authors.forename: Igor
authors.initials: I
authors.lastname: Dudich
authors.forename: Yelena
authors.initials: Y
authors.lastname: Parfyonova
authors.forename: Mikhail
authors.initials: M
authors.lastname: Menshikov
mesh_terms: D045744:Cell Line, Tumor; D002633:Chemotaxis; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D000509:alpha-Fetoproteins / Q000502:physiology*
chemical_list: D043562:Receptors, G-Protein-Coupled; D000509:alpha-Fetoproteins; D017346:Protein Serine-Threonine Kinases; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D019206:GTP-Binding Protein alpha Subunits, Gi-Go