Arsenic trioxide reduces the expression of E2F1, cyclin E, and phosphorylation of PI3K signaling molecules in acute leukemia cells

Abstract

Arsenic trioxide (ATO) has been used for the treatment of acute promyelocytic leukemia (APL). Although ATO modulates cell cycle progression and apoptosis in APL cells, its exact mechanism of action remains elusive. In this research, we investigated its effects on E2F1, cyclin E, p53, pRb, and PI3K signaling molecules by western blotting, immunocytochemistry and/or confocal imaging. We found that ATO inhibited the proliferation of APL cells through down‐regulation of E2F1 and cyclin E expression, and stimulation of pRb. It also reduced the interaction of pRb and E2F1with binding to the E2F1 promoter, by stimulating pRb association. ATO also effected the phosphorylation of pRb at S608 and T373 residues and association of E2F1, pRb, and p53, simultaneously. However, in p53‐knockdown NB4 cells, ATO did not significantly reduce E2F1 and cyclin E expression. Our findings demonstrate that ATO inhibits APL cell growth through reduced expression of E2F1, cyclin E, and stimulation of pRb. It also effected both interaction and association of E2F1, pRb, and p53 by phosphorylation of pRb at T373 and S608 residues and reduced phosphorylation of PI3K signaling molecules. This novel mode of action of ATO in APL cells may be useful for designing new APL drugs.

p53 as a unique target of action of cisplatin in acute leukaemia cells

“…From our previous study, we found that ATO activates p53 through a downregulation of complex molecules in the tissues of APL mice 47 . Our new findings reveal that CDDP treatment significantly disrupted MDM2‐DAXX‐HAUSP and downregulated the association and expression of its constituents/molecules in NB4 cells, KG1a cells, and APL mice liver tissue (Figure 3A–E).…”

“…2,4,[13][14][15][16] From our previous study, we found that ATO activates p53 through a downregulation of complex molecules in the tissues of APL mice. 47 Our new findings reveal that CDDP treatment significantly disrupted MDM2-DAXX-HAUSP and downregulated the association and expression of its constituents/molecules in NB4 cells, KG1a cells, and APL mice liver tissue (Figure 3A-E). Several other studies have provided evidence that DNA damage and stress signal is transmitted from protein kinase (ATM and ATR) and its downstream CHK1 and CHK2 target phosphorylation at different residues in cancer cells.…”

Arsenic Trioxide Decreases Lymphangiogenesis by Inducing Apoptotic Pathways and Inhibition of Important Endothelial Cell Receptors

“…In addition, ATO has been shown to suppress anti-apoptotic genes (e.g., survivin, bcl-2 and Mcl-1) and to upregulate pro-apoptotic genes (e.g., Puma, Bax and NOXA) in various tumor cell lines, such as leukemia, glioma and rhabdomyosarcoma [9][10][11]. Furthermore, ATO regulates the expression of proteins implicated in cell cycle control and differentiation (e.g., p21 WAF1/KIP1 , p53, E2F1, HoxC9, cyclin E and D) [12][13][14]. Moreover, ATO has been reported to suppress angiogenesis by inhibiting pro-angiogenic factors, such as vascular endothelial growth factor (VEGF), Notch1 and VEGFR-2 [15,16].…”