Department of Morphology and Embryology and LTTA Centre, University of Ferrara, Ferrara, Italy.
Mol Carcinog. 2014 Jun;53(6):498-504. doi: 10.1002/mc.21985. Epub 2012 Nov 28.
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.
MDM2/p53 相互作用的小分子抑制剂 Nutlin-3 是一种很有前途的抗癌药物，对多种癌症具有活性，包括急性髓系白血病 (AML)。先前的研究表明，Nutlin-3 可在癌细胞中诱导凋亡和细胞周期停滞，而在正常细胞中显示出低/无细胞毒性。然而，对于正常细胞，癌细胞中选择性促凋亡活性的原因尚不完全清楚。在这项研究中，我们比较了两种 p53（野生型）AML 细胞系 OCI-AML3 和 MOLM 与原代正常外周血单核细胞 (PBMC) 中几种已知 p53 靶基因的诱导。在 AML 细胞系和正常 PBMC 中均被激活的几种 p53 靶基因（BBC3、BAX、MDM2、FAS、CDKN1A、GDF15、GADD45A、TNFRSF10B、TP53I3/PIG3）中，只有 TP53I3/PIG3 在 MOLM 和 OCI-AML3 中被选择性激活，而在 PBMC 中则没有。TP53I3/PIG3 在介导 Nutlin-3 的凋亡活性方面的重要作用，通过针对 TP53I3/PIG3 的 siRNA 敲低实验得到了强调，这导致 Nutlin-3 的促凋亡活性显著降低。
