title: Copper egress is induced by PMA in human THP-1 monocytic cell line.
abstract: Copper egress is an essential regulator of the kinetics of cellular copper and is primarily regulated by ATP7A, a copper-transporting P-type ATPase. However, little is known under which physiological condition copper egress is induced and its molecular consequence. In current manuscript, using THP-1 cells, a human monocytic cell line, we found that ATP7A expression was increased in cells exposed to phorbol-12-myristate-13-acetate (PMA), a potent inducer of neovascularization and cancer. Inductively coupled plasma mass spectrometry revealed that PMA also induced copper egress. Inhibition of ATP7A expression using small interfering RNA abrogated PMA induced copper egress. PMA treatment in THP-1 cells resulted in increased expression of matrix metalloproteinase (MMP) 9 and vascular endothelial growth factor receptor 1 (VEGFR1), whereas inhibition of ATP7A resulted in suppression of PMA-induced expression of VEGFR1, but not MMP9. Finally, addition of exogenous copper into the conditioned medium did not change VEGFR1 expression in THP-1 cells. Collectively, we demonstrate that PMA induces copper egress in THP-1 cells, which is regulated by ATP7A, and ATP7A regulates VEGFR1 expression. Considering the involvement of copper in neovascularization, our current finding provides the potential evidence to interpret the molecular mechanism.
authors.affiliation: Division of Cardiovascular Disease, College of Medicine, University of Cincinnati, 231 Albert Sabin Way, Mail Location 0542, Cincinnati, OH 45267, USA.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Afton
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Caruso
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Britigan
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Qin
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D027682:Cation Transport Proteins / Q000378:metabolism; D002460:Cell Line; D003300:Copper / Q000378:metabolism* / Q000494:pharmacology; D000073840:Copper-Transporting ATPases; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D017136:Ion Transport / Q000187:drug effects* / Q000502:physiology; D007700:Kinetics; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism
chemical_list: D027682:Cation Transport Proteins; D003300:Copper; D040281:Vascular Endothelial Growth Factor Receptor-1; D020780:Matrix Metalloproteinase 9; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases; D013755:Tetradecanoylphorbol Acetate