title: Role of Smac in determining the chemotherapeutic response of esophageal squamous cell carcinoma.
abstract: OBJECTIVE
  Second mitochondria-derived activator of caspase (Smac) regulates chemotherapy-induced apoptosis. Smac mimetics have been tested in clinical trials as chemosensitizers. We determined the role of Smac in modulating the chemosensitivity of esophageal squamous cell carcinoma (ESCC).
  
  
  METHODS
  Smac expression was evaluated in tissues from ESCC patients with differential chemotherapeutic responses. The effects of Smac knockdown and Smac mimetics on the chemosensitivity of ESCC cells and the molecular mechanisms by which Smac and Smac mimetics modulate chemosensitivity were determined. The therapeutic responses of ESCC cells with different Smac statuses were compared using xenograft models.
  
  
  RESULTS
  We found that Smac was significantly downregulated in most ESCC samples (36.8%, 25/68, P = 0.001), and Smac expression differed significantly (P < 0.05) between chemosensitive and chemoresistant tumors. The associations of tested factors and their responses were examined using logistic regression analysis. In ESCC cells treated with cisplatin, a common chemotherapeutic drug, Smac and cytochrome c were released from mitochondria, and caspase-3 and caspase-9 were activated. Knockdown of Smac abrogated cisplatin-induced apoptosis, mitochondrial dysfunction, cytochrome c release, and caspase activation. Smac deficiency also reduced the effect of cisplatin on long-term cell viability, and led to cisplatin resistance in xenograft tumors in vivo. LBW242, a small molecule Smac mimetic, enhanced cisplatin-induced apoptosis and caspase activation and restored cisplatin sensitivity in Smac-deficient cells.
  
  
  CONCLUSIONS
  Our data suggested that downregulation of Smac may be a chemoresistance mechanism in ESCC. Combinations of Smac mimetics with chemotherapeutic agents may have therapeutic benefits for the treatment of esophageal cancer.
authors.affiliation: State Key Laboratory of Molecular Oncology and Departments of Medicine of Oncology, Cancer Institute & Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.forename: Lanping
authors.initials: L
authors.lastname: Zhou
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Jian
authors.initials: J
authors.lastname: Yu
authors.forename: Qimin
authors.initials: Q
authors.lastname: Zhan
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Xiaohang
authors.initials: X
authors.lastname: Zhao
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016015:Logistic Models; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology; D034622:RNA Interference; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; C522798:LBW242; D024101:Mitochondrial Proteins; D009842:Oligopeptides; D045304:Cytochromes c; D020169:Caspases; D002945:Cisplatin