title: Phenylarsine oxide induces apoptosis in Bax- and Bak-deficient cells through upregulation of Bim.
abstract: OBJECTIVE
  Bax and Bak are regarded as key mediators for cytochrome c (Cyt c) release and apoptosis. Loss of Bax or Bak is often reported in human cancers and renders resistance of these cancerous cells to chemotherapy. Here, we investigated that phenylarsine oxide (PAO) could induce Bax/Bak-independent apoptosis.
  
  
  METHODS
  Annexin V/propidium iodide (PI) staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and caspase activation assays were conducted to detect apoptosis in Bax/Bak-deficient mouse embryonic fibroblasts (MEF) and HCT116 bax(-/-) colorectal cancer cells. Cyt c release and Bim expression were assessed by Western blotting and immunostaining. Bim was stably knocked down by short hairpin RNA. Immunoprecipitation was applied to detect the interaction between Bim and Bcl-2. Both subcutaneous and colorectal orthotopic tumor implantation models were used in nude mice to investigate the effect of PAO in vivo.
  
  
  RESULTS
  PAO triggered Cyt c release and apoptosis in a Bax/Bak-independent manner. Bim and Bcl-2 were both involved in this process. PAO augmented the expression of Bim and strengthened the interaction between Bim and Bcl-2. Furthermore, PAO attenuated the growth of Bax-deficient cancer cells in vivo.
  
  
  CONCLUSIONS
  Our results showed that PAO induced apoptosis in chemotherapy-resistant cancer cells, which suggests that PAO has the potential to serve as a chemotherapeutic agent for Bax- and Bak-deficient cancers.
authors: Joint Laboratory of Apoptosis and Cancer Biology, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors: Biyun
authors: B
authors: Ni
authors: Qi
authors: Q
authors: Ma
authors: Baowei
authors: B
authors: Li
authors: Lixia
authors: L
authors: Zhao
authors: Yong
authors: Y
authors: Liu
authors: Yushan
authors: Y
authors: Zhu
authors: Quan
authors: Q
authors: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001152:Arsenicals / Q000494:pharmacology*; D000072224:Bcl-2-Like Protein 11; D015153:Blotting, Western; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000502:physiology*; D051028:bcl-2-Associated X Protein / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D001152:Arsenicals; C000606775:BCL2L11 protein, human; C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D010975:Platelet Aggregation Inhibitors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C029341:oxophenylarsine