title: Apollon modulates chemosensitivity in human esophageal squamous cell carcinoma.
abstract: Patients with esophageal squamous cell carcinoma (ESCC) are often diagnosed with advanced diseases that respond poorly to chemotherapy. Here we reported that Apollon, a membrane-associated inhibitor of apoptosis protein, was overexpressed in ESCC cell lines and clinical ESCC tissues, and Apollon overexpression clinically correlated with poor response to chemotherapy (P = 0.001), and short overall survival (P = 0.021). Apollon knockdown increased cisplatin/docetaxel-induced apoptosis, mitochondrial dysfunction and cytochrome c release in two ESCC cell lines. Apollon knockdown potentiated cisplatin/docetaxel-induced long-term cell growth inhibition, and enhanced chemosensitivity of ESCC cells to cisplatin/docetaxel in xenograft tumor models. Apollon knockdown also enhanced cisplatin/docetaxel-induced activation of caspase-8 (extrinsic pathway) and caspase-9 (intrinsic pathway) in ESCC cells and xenograft tumor models. Mechanism studies revealed that the effect of Apollon on chemosensitivity is mainly mediated by Smac. Apollon expression strongly and negatively correlated with Smac expression in clinical ESCC tissues (P = 0.001). Apollon targeted Smac for degradation in ESCC cells. The effect of Apollon on chemosensitivity was reversed by Smac knockdown in ESCC cells. Taken together, our data show association of Apollon expression with chemotherapeutic response in ESCC, and provide a strong rationale for combining Apollon antagonism with chemotherapy to treat ESCC.
authors.affiliation: Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China. These authors contributed equally to this work.
authors.forename: Si
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology and Hepatology, Zhongshan Hospital, Shanghai Institute of Liver Disease, Fudan University, Shanghai, China. These authors contributed equally to this work.
authors.forename: Wenqing
authors.initials: W
authors.lastname: Tang
authors.affiliation: Department of Gastroenterology and Hepatology, Zhongshan Hospital, Shanghai Institute of Liver Disease, Fudan University, Shanghai, China.
authors.forename: Shuqiang
authors.initials: S
authors.lastname: Weng
authors.affiliation: Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors.forename: Xijun
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Gastrointestinal Anal Surgery and Institute of Gastroenterology, the Third Affiliated Hospital, Nanchang University, Nanchang, China.
authors.forename: Benqiang
authors.initials: B
authors.lastname: Rao
authors.affiliation: Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Gu
authors.affiliation: Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors.forename: She
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology and Hepatology, Zhongshan Hospital, Shanghai Institute of Liver Disease, Fudan University, Shanghai, China.
authors.forename: Xizhong
authors.initials: X
authors.lastname: Shen
authors.affiliation: Department of Gastroenterology and Hepatology, Zhongshan Hospital, Shanghai Institute of Liver Disease, Fudan University, Shanghai, China.
authors.forename: Ruyi
authors.initials: R
authors.lastname: Xue
authors.affiliation: Department of Gastroenterology and Hepatology, Zhongshan Hospital, Shanghai Institute of Liver Disease, Fudan University, Shanghai, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Dong
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D015536:Down-Regulation; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D023041:Xenograft Model Antitumor Assays
chemical_list: C401541:BIRC6 protein, human; D051034:Inhibitor of Apoptosis Proteins