title: Mechanisms of anti-leukemic activity of the Bcl-2 homology domain-3 mimetic S1.
abstract: Most of leukemia exhibits inherent overexpressed Bcl-2-like proteins. Small molecule S1 is a BH3 mimetic discovered by our previous studies. The aim of this study is to dissect the details of apoptosis signaling induced by S1 in acute myeloid leukaemia (AML) cells and to provide a molecular basis for the use of S1 in AML treatment. The anti-leukemic activity of S1 was evaluated in three cultured AML cell lines and eight patient samples. S1 induced apoptosis via an intrinsic apoptosis pathway by the disruption of protein-protein interactions of Bcl-2 family members and triggered the activation of Bax and Bak in AML cells. For the first time, we report that S1 can release pro-apoptotic protein from Bcl-XL and selectively inhibits colony formation of primary AML cells. Bak activation and release determined S1 sensitivity in AML cells. Furthermore, S1-induced apoptosis was largely reduced in cells with shRNA-mediated downregulation of Bak but not Bax. The combination of S1 with PD98059 can inhibit Bcl-2 phosphorylation and enhance Bak release from Bcl-2. Our study identified Bak as a key mediator of S1-induced intrinsic apoptosis in AML cells. Moreover, our data suggest that Bcl-2 phosphorylation plays an anti-apoptotic role in S1-induced apoptosis. This study could contribute not only to the future clinical development of S1, but also the rational use of other pan-Bcl-2 inhibitors, alone or in combination with kinase inhibitor-based strategies.
authors.affiliation: State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, China; School of Life Science and Technology, Dalian University of Technology, Dalian, China.
authors.forename: Yubo
authors.initials: Y
authors.lastname: Liu
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Li
authors.forename: Ting
authors.initials: T
authors.lastname: Song
authors.forename: Zuguang
authors.initials: Z
authors.lastname: Xue
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D018716:Molecular Mimicry; D014411:Neoplastic Stem Cells / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C494772:BAK1 protein, human; D005419:Flavonoids; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: AML; BH3 mimetic; Bak-dependent