title: Selective induction of TP53I3/p53-inducible gene 3 (PIG3) in myeloid leukemic cells, but not in normal cells, by Nutlin-3.
abstract: The small molecule inhibitor of the MDM2/p53 interaction Nutlin-3 is a promising anti-cancer agent, which exhibits activity against a variety of cancers, including acute myeloid leukemia (AML). Previous studies have shown that Nutlin-3 variably induces apoptosis and cell cycle arrest in cancer cells while it shows low/absent cytotoxicity in normal cells. However, the reason for the selective pro-apoptotic activity in cancer cells with respect to normal counterparts is incompletely understood. In this study, we have compared the induction of several known target genes of p53 in two p53(wild-type) AML cell lines, OCI-AML3 and MOLM, in comparison with primary normal peripheral blood mononuclear cells (PBMC). Among several p53-target genes activated both in AML cell lines and normal PBMC (BBC3, BAX, MDM2, FAS, CDKN1A, GDF15, GADD45A, TNFRSF10B, TP53I3/PIG3), only TP53I3/PIG3 was selectively activated in MOLM and OCI-AML3, but not in PBMC. The important role of TP53I3/PIG3 in mediating the apoptotic activity of Nutlin-3 was underlined by knock-down experiments with siRNA specific for TP53I3/PIG3, which resulted in a significant decrease in the pro-apoptotic activity of Nutlin-3.
authors.affiliation: Department of Morphology and Embryology and LTTA Centre, University of Ferrara, Ferrara, Italy.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Voltan
authors.forename: Paola
authors.initials: P
authors.lastname: Secchiero
authors.forename: Federica
authors.initials: F
authors.lastname: Corallini
authors.forename: Giorgio
authors.initials: G
authors.lastname: Zauli
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology* / Q000633:toxicity; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology* / Q000633:toxicity; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D010879:Piperazines; D011518:Proto-Oncogene Proteins; C411296:TP53I3 protein, human; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3