Abstract
Abstract Both all trans retinoic acid (ATRA) and arsenic trioxide (ATO) induce complete remission in acute promyelocytic leukemia (APL) patients. Using the APL derived NB4 cell line containing the PML-RARα fusion protein it has been found that ATRA induced differentiation while ATO mainly induced apoptosis. Previously it has been reported that the antiapoptotic proteins Bcl-2 and Bfl-1/A1 were regulated during ATRA-induced differentiation process in APL cells. However, the regulation of Mcl-1, a major antiapoptotic protein required during myeloid granulocyte differentiation, has not been determined. Recently it has been shown that ERK phosphorylates Mcl-1 and regulates its stability. The regulation of Mcl-1 and p-ERK by ATRA and ATO were investigated in NB4 and its subclone R4 cells, HL-60 and its subclone HL-60/Res cells. Both NB4 and R4 cells contain PML-RARα while HL-60 and HL-60/Res cells contain RARα. However, the ATRA binding domain in PML-RARα and RARα is mutant in R4 and HL-60/Res cells, respectively. The levels of Mcl-1 were induced by ATRA in both NB4 and HL-60 cells, but not in R4 cells nor HL-60/Res cells. The induction of Mcl-1 in NB4 and HL-60 cells correlated with the induction of differentiation and the increased level of p-ERK. Unlike ATRA treatment, ATO treatment decreased the levels of Mcl-1 in both NB4 and R4 cells, but not in HL-60 nor in HL-60/Res cells, which correlated with the induction of apoptosis and down-regulation of p-ERK. Both NB4 and R4 cells contain PML-RARα which is degraded by ATO, suggesting that PML-RARα plays a role in ATO-mediated down-regulation of Mcl-1. To test the effect of PML-RARα on the regulation of Mcl-1 after ATO treatment, U937/PR9 cells with the inducible expression of PML-RARα were used. Expression of PML-RARα increased the levels of Mcl-1 and p-ERK. ATO treatment decreased the levels of both Mcl-1 and p-ERK. These data suggest that ATRA increases the level of Mcl-1 through activating ERK due to overcoming PML-RARα transcriptional repression and activating RARα while ATO decreases the level of Mcl-1 through inactivation of ERK due to inducing degradation of PML-RARα. The increased level of Mcl-1 after ATRA treatment protects against cell death and promotes differentiation while the decreased level of Mcl-1 after ATO-treatment sensitizes apoptosis induction. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5479. doi:10.1158/1538-7445.AM2011-5479
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