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.
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Abbreviations
- ICP-MS:
-
Inductively coupled plasma mass spectrometry
- MMP:
-
Matrix metalloproteinase
- PMA:
-
Phorbol-12-myristate-13-acetate
- VEGF:
-
Vascular endothelial growth factor
- VEGFR1:
-
VEGF receptor 1
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Acknowledgments
This work was supported by a National Scientist Development Grant (0835268N) from the American Heart Association, and a URC Faculty Development Award from the University of Cincinnati. We thank Dr. Tohru Fukai (University of Illinois at Chicago) for his helpful discussion.
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Afton, S.E., Caruso, J.A., Britigan, B.E. et al. Copper egress is induced by PMA in human THP-1 monocytic cell line. Biometals 22, 531–539 (2009). https://doi.org/10.1007/s10534-009-9210-y
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DOI: https://doi.org/10.1007/s10534-009-9210-y