TY - JOUR
T1 - Arsenic trioxide (ATO) and MEK1 inhibition synergize to induce apoptosis in acute promyelocytic leukemia cells
AU - Lunghi, P.
AU - Tabilio, A.
AU - Lo-Coco, F.
AU - Pelicci, P.
AU - Bonati, A.
PY - 2005/2
Y1 - 2005/2
N2 - Recent studies suggest that components of the prosurvival signal transduction pathways involving the Ras-mitogen-activated protein kinase (MAPK) can confer an aggressive, apoptosis-resistant phenotype to leukemia cells. In this study, we report that acute promyelocytic leukemia (APL) cells exploit the Ras-MAPK activation pathway to phosphorylate at Ser112 and to inactivate the proapoptotic protein Bad, delaying arsenic trioxide (ATO)-induced apoptosis. Both in APL cell line NB4 and in APL primary blasts, the inhibition of extracellular signal-regulated kinases 1/2 (ERK1/2) and Bad phosphorylation by MEK1 inhibitors enhanced apoptosis in ATO-treated cells. We isolated an arsenic-resistant NB4 subline (NB4-AsR), which showed stronger ERK1/2 activity (2.7-fold increase) and Bad phosphorylation (2.4-fold increase) compared to parental NB4 cells in response to ATO treatment. Upon ATO exposure, both NB4 and NB4-AsR cell lines doubled protein levels of the death antagonist Bcl-xL, but the amount of free Bcl-xL that did not heterodimerize with Bad was 1.8-fold greater in NB4-AsR than in the parental line. MEK1 inhibitors dephosphorylated Bad and inhibited the ATO-induced increase of Bcl-xL, overcoming ATO resistance in NB4-AsR. These results may provide a rationale to develop combined or sequential MEK1 inhibitors plus ATO therapy in this clinical setting.
AB - Recent studies suggest that components of the prosurvival signal transduction pathways involving the Ras-mitogen-activated protein kinase (MAPK) can confer an aggressive, apoptosis-resistant phenotype to leukemia cells. In this study, we report that acute promyelocytic leukemia (APL) cells exploit the Ras-MAPK activation pathway to phosphorylate at Ser112 and to inactivate the proapoptotic protein Bad, delaying arsenic trioxide (ATO)-induced apoptosis. Both in APL cell line NB4 and in APL primary blasts, the inhibition of extracellular signal-regulated kinases 1/2 (ERK1/2) and Bad phosphorylation by MEK1 inhibitors enhanced apoptosis in ATO-treated cells. We isolated an arsenic-resistant NB4 subline (NB4-AsR), which showed stronger ERK1/2 activity (2.7-fold increase) and Bad phosphorylation (2.4-fold increase) compared to parental NB4 cells in response to ATO treatment. Upon ATO exposure, both NB4 and NB4-AsR cell lines doubled protein levels of the death antagonist Bcl-xL, but the amount of free Bcl-xL that did not heterodimerize with Bad was 1.8-fold greater in NB4-AsR than in the parental line. MEK1 inhibitors dephosphorylated Bad and inhibited the ATO-induced increase of Bcl-xL, overcoming ATO resistance in NB4-AsR. These results may provide a rationale to develop combined or sequential MEK1 inhibitors plus ATO therapy in this clinical setting.
KW - Acute Promyelocytic leukemia
KW - Arsenic trioxide
KW - Bad phosphorylation
KW - Leukemia cells apoptosis
KW - MEK1 inhibition
KW - MEK1 sIRNA
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UR - http://www.scopus.com/inward/citedby.url?scp=13544266545&partnerID=8YFLogxK
U2 - 10.1038/sj.leu.2403585
DO - 10.1038/sj.leu.2403585
M3 - Article
C2 - 15538402
AN - SCOPUS:13544266545
VL - 19
SP - 234
EP - 244
JO - Leukemia
JF - Leukemia
SN - 0887-6924
IS - 2
ER -