Oncotarget

Research Papers:

Apollon modulates chemosensitivity in human esophageal squamous cell carcinoma

Si Zhang, Wenqing Tang, Shuqiang Weng, Xijun Liu, Benqiang Rao, Jianxin Gu, She Chen, Qun Wang, Xizhong Shen, Ruyi Xue and Ling Dong _

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Oncotarget. 2014; 5:7183-7197. https://doi.org/10.18632/oncotarget.2293

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Abstract

Si Zhang1,*, Wenqing Tang2,*, Shuqiang Weng2, Xijun Liu1, Benqiang Rao3, Jianxin Gu1, She Chen1, Qun Wang4, Xizhong Shen2, Ruyi Xue2 and Ling Dong2

1 Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China

2 Department of Gastroenterology and Hepatology, Zhongshan Hospital, Shanghai Institute of Liver Disease, Fudan University, Shanghai, China

3 Department of Gastrointestinal Anal Surgery and Institute of Gastroenterology, the Third Affiliated Hospital, Nanchang University, Nanchang, China

4 Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China

* These authors contributed equally to this work

Correspondence:

Ling Dong , email:

Ruyi Xue , email:

Keywords: apoptosis, cancer, IAPs, prognosis, Smac

Received: May 19, 2014 Accepted: July 31, 2014 Published: July 31, 2014

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.


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