title: Annonaceous acetogenin mimic AA005 induces cancer cell death via apoptosis inducing factor through a caspase-3-independent mechanism.
abstract: BACKGROUND
  Annonaceous acetogenins are a family of natural products with antitumor activities. Annonaceous acetogenin mimic AA005 reportedly inhibits mammalian mitochondrial NADH-ubiquinone reductase (Complex I) and induces gastric cancer cell death. However, the mechanisms underlying its cell-death-inducing activity are unclear.
  
  
  METHODS
  We used SW620 colorectal adenocarcinoma cells to study AA005 cytotoxic activity. Cell deaths were determined by Trypan blue assay and flow cytometry, and related proteins were characterized by western blot. Immunofluorescence and subcellular fractionation were used to evaluate AIF nuclear translocation. Reactive oxygen species were assessed by using redox-sensitive dye DCFDA.
  
  
  RESULTS
  AA005 induces a unique type of cell death in colorectal adenocarcinoma cells, characterized by lack of caspase-3 activation or apoptotic body formation, sensitivity to poly (ADP-ribose) polymerase inhibitor Olaparib (AZD2281) but not pan-caspase inhibitor Z-VAD.fmk, and dependence on apoptosis-inducing factor (AIF). AA005 treatment also reduced expression of mitochondrial Complex I components, and leads to accumulation of intracellular reactive oxygen species (ROS) at the early stage. Blocking ROS formation significantly suppresses AA005-induced cell death in SW620 cells. Moreover, blocking activation of RIP-1 by necroptosis inhibitor necrotatin-1 inhibits AIF translocation and partially suppresses AA005-induced cell death in SW620 cells demonstrating that RIP-1 protein may be essential for cell death.
  
  
  CONCLUSIONS
  AA005 may trigger the cell death via mediated by AIF through caspase-3 independent pathway. Our work provided new mechanisms for AA005-induced cancer cell death and novel clues for cancer treatment via AIF dependent cell death.
authors.affiliation: Center for Molecular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. hb054080108@126.com.
authors.forename: Bing
authors.initials: B
authors.lastname: Han
authors.affiliation: Center for Molecular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. tongdanwang@shsmu.edu.cn.
authors.forename: Tong-Dan
authors.initials: TD
authors.lastname: Wang
authors.affiliation: Center for Molecular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. smshen01@sibs.ac.cn.
authors.forename: Shao-Ming
authors.initials: SM
authors.lastname: Shen
authors.affiliation: Center for Molecular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. yy@shsmu.edu.cn.
authors.forename: Yun
authors.initials: Y
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Coordination Chemistry, Institute of Chemical Biology and Drug Innovation, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210093, P. R. China. maochan1025@126.com.
authors.forename: Chan
authors.initials: C
authors.lastname: Mao
authors.affiliation: State Key Laboratory of Coordination Chemistry, Institute of Chemical Biology and Drug Innovation, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210093, P. R. China. Yao@nju.edu.cn.|Shanghai Universities E-Institute for Chemical Biology, Shanghai, 200025, China. Yao@nju.edu.cn.
authors.forename: Zhu-Jun
authors.initials: ZJ
authors.lastname: Yao
authors.affiliation: Center for Molecular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. jywangls@shsmu.edu.cn.|Shanghai Universities E-Institute for Chemical Biology, Shanghai, 200025, China. jywangls@shsmu.edu.cn.
authors.forename: Li-Shun
authors.initials: LS
authors.lastname: Wang
mesh_terms: D054378:Acetogenins / Q000737:chemistry / Q000494:pharmacology*; D051033:Apoptosis Inducing Factor / Q000096:biosynthesis*; D053148:Caspase 3; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005233:Fatty Alcohols / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D020298:U937 Cells
chemical_list: C483824:AA005; D054378:Acetogenins; D051033:Apoptosis Inducing Factor; D005233:Fatty Alcohols; D007783:Lactones; D017382:Reactive Oxygen Species; D053148:Caspase 3