title: Triptolide inhibits MDM2 and induces apoptosis in acute lymphoblastic leukemia cells through a p53-independent pathway.
abstract: Triptolide, a natural product derived from the Chinese plant Tripterygium wilfordii, is reported to exhibit antitumor effects in a broad range of cancers. The antitumor activity of triptolide is associated with its biologic activities, as it inhibits various proproliferative or antiapoptotic factors that are dominantly expressed in given types of cancer cells. Herein, we show that triptolide induced apoptosis in a subgroup of acute lymphoblastic leukemia (ALL) cells overexpressing the MDM2 oncoprotein by inhibiting MDM2 expression. More specifically, we found that triptolide inhibited MDM2 at the transcriptional level by suppressing its mRNA synthesis. This MDM2 inhibition led in turn to increased levels of p53 protein; however, p53 functionality was not activated due to the fact that triptolide-treated cells lacked induction of p21 and PUMA as well as in G(1) cell-cycle arrest. Triptolide-mediated downregulation of MDM2 increased inhibition of X-linked inhibitor of apoptosis protein (XIAP), its translational target, in a manner distinct from reactions to cellular stress and DNA-damaging agent ionizing radiation that induce XIAP due to p53-activated MDM2. These results suggest that increased inhibition of XIAP due to downregulation of MDM2 may play a critical role in triptolide-induced apoptosis in MDM2-overexpressing cancers.
authors.affiliation: Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Huang
authors.forename: Hailong
authors.initials: H
authors.lastname: Zhang
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.forename: Dan
authors.initials: D
authors.lastname: Tian
authors.forename: Lubing
authors.initials: L
authors.lastname: Gu
authors.forename: Muxiang
authors.initials: M
authors.lastname: Zhou
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002648:Child; D004224:Diterpenes / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000494:pharmacology; D006801:Humans; D010616:Phenanthrenes / Q000494:pharmacology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004224:Diterpenes; D004852:Epoxy Compounds; D010616:Phenanthrenes; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C001899:triptolide; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2