title: Smac mimetic compound LCL161 sensitizes esophageal carcinoma cells to radiotherapy by inhibiting the expression of inhibitor of apoptosis protein.
abstract: Currently, unresectable esophageal squamous cell carcinoma (ESCC) is primarily treated by chemoradiotherapy. However, the outcome has not improved significantly due to radioresistance of cancer cells. This study aimed to determine the radiosensitizing effect of LCL161, a novel second mitochondrial-derived activator of caspase (Smac) mimetic, in ESCC cells. ESCC cell lines were treated with LCL161 or radiation, alone or in combination. Cell proliferation was detected by MTT assay. Radiosensitization was evaluated by clonogenic survival assay. Cell apoptosis was detected by flow cytometry. The results showed that LCL161 potently sensitized ESCC cells to radiation with a sensitization enhancement ratio of 1.4-2.0. LCL161 increased radiation-induced DNA double-stranded breaks and promoted the apoptosis of ESCC cells, which could be abrogated by a pan-caspase inhibitor z-VAD-FMK. Furthermore, LCL161 decreased the level of cIAP1 in ESCC cells in a dose-dependent manner and synthesized with irradiation to promote the activation of caspase 8 and the upregulation of TNFα expression in ESCC cells. In conclusion, LCL161 acts as a strong radiosensitizer in human esophageal cancer cells by inhibiting the expression of cIAP1 and promoting the activation of caspase 8, leading to enhanced apoptosis.
authors.affiliation: Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Qin
authors.forename: Yun
authors.initials: Y
authors.lastname: Zuo
authors.forename: Xi
authors.initials: X
authors.lastname: Yang
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.forename: Liangliang
authors.initials: L
authors.lastname: Zhan
authors.forename: Liping
authors.initials: L
authors.lastname: Xu
authors.forename: Chi
authors.initials: C
authors.lastname: Zhang
authors.forename: Hongcheng
authors.initials: H
authors.lastname: Zhu
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.forename: Zheming
authors.initials: Z
authors.lastname: Liu
authors.forename: Guangzhou
authors.initials: G
authors.lastname: Tao
authors.forename: Shengbin
authors.initials: S
authors.lastname: Dai
authors.forename: Xizhi
authors.initials: X
authors.lastname: Zhang
authors.forename: Jianxin
authors.initials: J
authors.lastname: Ma
authors.forename: Jing
authors.initials: J
authors.lastname: Cai
authors.forename: Xinchen
authors.initials: X
authors.lastname: Sun
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D032701:Biomimetics; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D004938:Esophageal Neoplasms / Q000378:metabolism*; D000077277:Esophageal Squamous Cell Carcinoma; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases
chemical_list: D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; C574246:LCL161; D024101:Mitochondrial Proteins; D011838:Radiation-Sensitizing Agents; D013844:Thiazoles; C494833:BIRC2 protein, human; D044767:Ubiquitin-Protein Ligases