title: LCL161 increases paclitaxel-induced apoptosis by degrading cIAP1 and cIAP2 in NSCLC.
abstract: LCL161, a novel Smac mimetic, is known to have anti-tumor activity and improve chemosensitivity in various cancers. However, the function and mechanisms of the combination of LCL161 and paclitaxel in non-small cell lung cancer (NSCLC) remain unknown.
  
  
  
  Cellular inhibitor of apoptotic protein 1 and 2 (cIAP1&2) expression in NSCLC tissues and adjacent non-tumor tissues were assessed by immunohistochemistry. The correlations between cIAP1&2 expression and clinicopathological characteristics, prognosis were analyzed. Cell viability and apoptosis were measured by MTT assays and Flow cytometry. Western blot and co-immunoprecipitation assay were performed to measure the protein expression and interaction in NF-kB pathway. siRNA-mediated gene silencing and caspases activity assays were applied to demonstrate the role and mechanisms of cIAP1&2 and RIP1 in lung cancer cell apoptosis. Mouse xenograft NSCLC models were used in vivo to determine the therapeutic efficacy of LCL161 alone or in combination with paclitaxel.
  
  
  
  The expression of cIAP1 and cIAP2 in Non-small cell lung cancer (NSCLC) tumors was significantly higher than that in adjacent normal tissues. cIAP1 was highly expressed in patients with late TNM stage NSCLC and a poor prognosis. Positivity for both cIAP1 and cIAP2 was an independent prognostic factor that indicated a poorer prognosis in NSCLC patients. LCL161, an IAP inhibitor, cooperated with paclitaxel to reduce cell viability and induce apoptosis in NSCLC cells. Molecular studies revealed that paclitaxel increased TNFα expression, thereby leading to the recruitment of various factors and the formation of the TRADD-TRAF2-RIP1-cIAP complex. LCL161 degraded cIAP1&2 and released RIP1 from the complex. Subsequently, RIP1 was stabilized and bound to caspase-8 and FADD, thereby forming the caspase-8/RIP1/FADD complex, which activated caspase-8, caspase-3 and ultimately lead to apoptosis. In nude mouse xenograft experiments, the combination of LCL161 and paclitaxel degraded cIAP1,2, activated caspase-3 and inhibited tumor growth with few toxic effects.
  
  
  
  Thus, LCL161 could be a useful agent for the treatment of NSCLC in combination with paclitaxel.
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China.
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department Two of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China.|Department of Surgical Oncology, Baoji Central Hospital, Baoji, Shaanxi, 721008, China.
authors.forename: Huangzhen
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department Two of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China.
authors.forename: Boxiang
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China.
authors.forename: Yimeng
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China.
authors.forename: Yamin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department Two of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department Two of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China.
authors.forename: Guodong
authors.initials: G
authors.lastname: Xiao
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China.
authors.forename: Kejun
authors.initials: K
authors.lastname: Nan
authors.affiliation: Department Two of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China. renhong@xjtu.edu.cn.
authors.forename: Hong
authors.initials: H
authors.lastname: Ren
authors.affiliation: Department Two of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China. sida.qin@yahoo.com.
authors.forename: Sida
authors.initials: S
authors.lastname: Qin
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000494:pharmacology; D000075747:Baculoviral IAP Repeat-Containing 3 Protein / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage* / Q000494:pharmacology; D011379:Prognosis; D059748:Proteolysis; D013844:Thiazoles / Q000008:administration & dosage* / Q000494:pharmacology; D016896:Treatment Outcome; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D051034:Inhibitor of Apoptosis Proteins; C574246:LCL161; D013844:Thiazoles; C494833:BIRC2 protein, human; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; D017239:Paclitaxel
keywords: Apoptosis; LCL161; NSCLC; Paclitaxel; cIAP