The Anti-Tumor Agent Sodium Selenate Decreases Methylated PP2A, Increases GSK3βY216 Phosphorylation, Including Tau Disease Epitopes and Reduces Neuronal Excitability in SHSY-5Y Neurons

Abstract

Selenium application as sodium selenate was repeatedly shown to have anti-carcinogenic properties by increasing levels of the serine/ threonine protein phosphatase 2A (PP2A) in cancer cells. PP2A has a prominent role in cell development, homeostasis, and in neurons regulates excitability. PP2A, GSK3β and Tau reside together in a complex, which facilitates their interaction and (dys)-function as has been reported for several neurological disorders. In this study we recorded maximum increase in total PP2A at 3 µM sodium selenate in a neuron cell line. In conjunction with these data, whole-cell electrophysiological studies revealed that this concentration had maximum effect on membrane potentials, conductance and currents. Somewhat surprisingly, the catalytically active form, methylated PP2A (mePP2A) was significantly decreased. In close correlation to these data, the phosphorylation state of two substrate proteins, sensitive to PP2A activity, GSK3β and Tau were found to be increased. In summary, our data reveal that sodium selenate enhances PP2A levels, but reduces catalytic activity of PP2A in a dose dependent manner, which fails to reduce Tau and GSK3β phosphorylation under physiological conditions, indicating an alternative route in the rescue of cell pathology in neurological disorders.

Metal-based compounds containing selenium: An appealing approach towards novel therapeutic drugs with anticancer and antimicrobial effects

“…Additionally, Se and Se-containing compounds have been demonstrated to have a potential synergistic effect in combination with other therapeutic agents [51][52][53], including metal complexes [54][55][56][57]. Likewise, ionic Se species, such as sodium selenite (Na 2 SO 3 ) [58], sodium selenate (Na 2 SO 4 ) [59,60], and sodium selenosulfate (NaSeSO 3 ) [61] have also been reported to possess therapeutic activity [62][63][64][65][66] and synergistic effects, especially for cancer treatment [67][68][69]. Therefore, all these factors highlight the potential applicability of Se-containing compounds and ionic forms of Se for the discovery of novel therapeutic drugs.…”

The Function of Selenium in Central Nervous System: Lessons from MsrB1 Knockout Mouse Models

“…It is also noteworthy that the methylation of PP2A, which could mediate the dephosphorylation of Tau [ 82 ], at the L309 of its catalytic subunit can potentially increase its activity [ 83 ]. However, it was reported recently that sodium selenite decreases the methylation of PP2A [ 84 ]. In addition, the selenium supplement could effectively inhibit ROS-mediated apoptotic neural precursor cell death [ 85 ] and promote the neurosphere viability, development, and differentiation [ 86 ].…”