title: Smac mimetic‑induced caspase‑independent necroptosis requires RIP1 in breast cancer.
abstract: There is an urgent requirement for the development of novel targeted therapies to treat breast cancer, which is the most comment type of malignancy among women. The evasion of apoptosis is a hallmark of cancer, and is often due to the upregulation of inhibitor of apoptosis proteins (IAPs) in tumor cells. Second mitochondrial‑derived activator of caspase/direct IAP‑binding protein with low PI is a natural IAP antagonist, which is found in the mitochondrion; this protein has a motif, which binds to a surface groove on the baculovirus IAP repeat domains of the IAPs. In the present study, the effects of the LCL161 Smac mimetic, a small molecule IAP antagonist, on breast cell lines was examined. The results from MTT and colony formation assays demonstrated that LCL161 markedly inhibited the proliferation and induced the apoptosis of MDA‑MB‑231 and MCF‑7 cell lines. As determined by western blotting, cIAP1 was degraded in the breast cancer cells, which occurred in an LCL161‑dependent manner. Upon caspase activation, LCL161 treatment induced necroptosis, another form of programmed cell death. The downregulation of receptor‑interacting protein kinase‑1 via small interfering RNA protected the cells from LCL161‑induced necroptosis. Taken together, the results of the present study showed that LCL161 can induce multiple forms of programmed cell death in breast cancer cells, and may thus offer promise as an anticancer agent in diverse genotypic backgrounds.
authors.affiliation: Department of Breast Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China.
authors.forename: Gongsheng
authors.initials: G
authors.lastname: Jin
authors.affiliation: Department of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, P.R. China.
authors.forename: Yadong
authors.initials: Y
authors.lastname: Lan
authors.affiliation: Department of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, P.R. China.
authors.forename: Fusheng
authors.initials: F
authors.lastname: Han
authors.affiliation: Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, P.R. China.
authors.forename: Mingliang
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, P.R. China.
authors.forename: Xianfu
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, P.R. China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, P.R. China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Hu
authors.affiliation: Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China.
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Breast Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China.
authors.forename: Benzhong
authors.initials: B
authors.lastname: Wang
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D061945:Caspase Inhibitors / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D061986:MCF-7 Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009336:Necrosis; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects; D016601:RNA-Binding Proteins / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: C119724:AGFG1 protein, human; D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D051034:Inhibitor of Apoptosis Proteins; C574246:LCL161; D028861:Nuclear Pore Complex Proteins; D016601:RNA-Binding Proteins; D013844:Thiazoles; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D020169:Caspases