Abstract
Trisenox (TX) has been used in the treatment of both de novo and relapsed acute promyelocytic leukemia (APL) patients. Using in vitro APL cell lines model in this research, we report on a new target of TX action through disruption of MDM2-DAXX-HAUSP complex, degradation of MDM2, and activation of p53 expression. TX–induced stress signal was transmitted by protein kinase (ATM & ATR) and phosphorylation of its downstream targets CHK1, CHK2, ATM, and ATR, respectively at the Ser 345, Thr68, Ser1981 and Ser 428 residues involved in complex disruption and p53 up-regulation. TX-activated p53 led to cell cycle arrest and apoptosis in APL cells. Our results showed that TX inhibited cell proliferation, disrupted complex molecules expression and association in APL cells. Our functional studies indicated that TX-induced down-regulation of complex molecules expression was mostly neutralized in both p53 knockdown NB4 cells and nutilin-3 treated KG1a cells. Hence our findings provide a functional evidence of TX action on cell cycle regulation and apoptosis in APL cells. This novel target of TX activity may be useful for designing new APL drugs.
Highlights
acute promyelocytic leukemia (APL), a blood cancer characterized by a translocation mutation between chromosome 15 and chromosome 17, strikes about 1,500 patients in the United States annually [1, 2]
We discovered a new target of action of TX through transmission of stress signal with protein kinases, and their downstream phosphorylation targets, disruption of Mouse double minute 2 homolog (MDM2)-Death-associated protein 6 (DAXX)-Herpesvirus-associated ubiquitinspecific protease (HAUSP) complex, and activation of p53 leading to cell cycle regulation and apoptosis in APL cell lines
TX induced accumulation of p53, p21 leading to cell cycle arrest, which was confirmed by a significant decrease www.oncotarget.com in the expression of ki67 and increase in the percentage of cell cycle arrest at S & G2 phase (Figure 2F)
Summary
APL, a blood cancer characterized by a translocation mutation between chromosome 15 and chromosome 17, strikes about 1,500 patients in the United States annually [1, 2]. ATRA and arsenic trioxide (ATO) combination is a targeted therapy without inclusion of chemotherapy This combination acts through induction of maturation of promyelocytes, apoptosis, and eradication of APL-initiating cells through degradation of PMLRARAα [15,16,17,18]. ATRA-ATO combination is not recommended to high risk refractory APL patients It does not work in RA-resistant promyelocytic leukemia zinc finger (PLZF)-RARα patients and may causes some sort of cardiovascular problems [8, 9, 12, 14]. TX is the preferred drug of choice for relapsed or refractory APL patients of all age groups It is used in both induction and consolidation therapy and high-risk APL patients with combination of ATRA and idarubicin, providing a maximum CR (~ 99 %) with longer survival rate [9, 12, 14, 21]. We discovered a new target of action of TX through transmission of stress signal with protein kinases, and their downstream phosphorylation targets, disruption of MDM2-DAXX-HAUSP complex, and activation of p53 leading to cell cycle regulation and apoptosis in APL cell lines
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