Treatment with arsenic trioxide (ATO) and MEK1 inhibitor activates the p73-p53AIP1 apoptotic pathway in leukemia cells.
Arsenic trioxide (ATO) induces differentiation and apoptosis of malignant cells in vitro and in vivo and has been used in the treatment of a variety of hematologic malignancies. We found that in NB4 acute promyelocytic and in K562 erythroleukemia cell lines treatment with the MEK1 inhibitors PD98059 and PD184352 greatly enhances apoptotic cell death induced by ATO alone. Combined treatment results in the induction of the p53AIP1 (p53-regulated apoptosis-inducing protein 1) gene in both cell lines. Because NB4 and K562 cell lines carry an inactive p53, we investigated the possible role of p73, a p53 paralogue that has been shown to regulate several p53 target genes including p21, Bax, and p53AIP1. We found that MEK1 inhibitors reduce the levels of dominant-negative (DeltaN) p73 proteins and promote the accumulation of endogenous p73alpha through its transcriptional activation and its tyrosine phosphorylation, resulting in p21 up-regulation and significant inhibition of cell growth. ATO reduces DeltaNp73 levels and promotes a p300-mediated acetylation of endogenous p73, thus favoring cell cycle arrest and apoptosis. Finally, the combined treatment with MEK1 inhibitors and ATO enhances the affinity of phosphoacetylated p73 for the p53AIP1 promoter in vivo, as determined by chromatin immunoprecipitation experiments, leading to p53AIP1 up-regulation and increased apoptosis.
Lunghi
Paolo
P
Dipartimento di Scienze Cliniche, Via Gramsci 14, 43100 Parma, Italy.
Costanzo
Antonio
A
Levrero
Massimo
M
Bonati
Antonio
A
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D016147:Genes, Tumor Suppressor; D006801:Humans; D066298:In Vitro Techniques; D020014:K562 Cells; D004915:Leukemia, Erythroblastic, Acute / Q000188:drug therapy*; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D009687:Nuclear Proteins / Q000378:metabolism*; D010087:Oxides / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism*; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins
C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D001152:Arsenicals; D001549:Benzamides; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D009687:Nuclear Proteins; D010087:Oxides; C414742:P53AIP1 protein, human; D011506:Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C000606369:delta Np73 protein, human; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D000077237:Arsenic Trioxide; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one