66 - Copper Transporter, Antioxidant-1 (Atox-1), Modulates Redox Homeostasis during Phorbol-Ester-Induced THP-1 Cell Differentiation

Abstract

Copper (Cu), an essential micronutrient, is involved in vascular remodeling, and its bioavailability regulated by Cu transporter proteins, such as ATP7A and antioxidant-1 (Atox-1). Superoxide dismutase 3 (SOD3), which has a Cu ion in the active site, plays a pivotal role in the redox homeostasis, and its loss exacerbates vascular diseases. We have reported that SOD3 expression induces in phorbol ester (TPA)-treated human monocytic THP-1 cells; however, the involvement of Cu ion in its induction is entirely unknown. TPA stimulation in THP-1 cells induced ATP7 expression and Atox-1 nuclear translocation through PKC and MEK/ERK signaling. According to the previous report, which shows that Atox-1 functions as a transcription factor for SOD3, we demonstrated the role of Atox-1 in TPA-elicited SOD3 induction. Overexpression of Atox-1 protein enhanced TPA-elicited SOD3 expression, and knockdown of Atox-1 with siRNA suppressed its expression, suggesting that Atox-1 plays a pivotal role in SOD3 regulation in THP-1 cells. Additionally, knockdown of Atox-1 suppressed mRNA expression of gp91phox, an essential component of NOX2. Overall, we have determined that intracellular Cu modulation via its transporter might regulate redox homeostasis in THP-1 cells by the alteration in expression of SOD3 and gp91phox.