RRC ID 69319
Author Zhang S, Tang W, Weng S, Liu X, Rao B, Gu J, Chen S, Wang Q, Shen X, Xue R, Dong L.
Title Apollon modulates chemosensitivity in human esophageal squamous cell carcinoma.
Journal Oncotarget
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.
Volume 5(16)
Pages 7183-97
Published 2014-8-30
DOI 10.18632/oncotarget.2293
PII 2293
PMID 25216531
PMC PMC4196194
MeSH Animals Apoptosis / physiology Carcinoma, Squamous Cell / drug therapy* Carcinoma, Squamous Cell / genetics Carcinoma, Squamous Cell / metabolism* Carcinoma, Squamous Cell / pathology Cell Line, Tumor Cell Proliferation / physiology Down-Regulation Esophageal Neoplasms / drug therapy* Esophageal Neoplasms / genetics Esophageal Neoplasms / metabolism* Esophageal Neoplasms / pathology Esophageal Squamous Cell Carcinoma Humans Inhibitor of Apoptosis Proteins / biosynthesis* Inhibitor of Apoptosis Proteins / genetics Inhibitor of Apoptosis Proteins / metabolism Male Mice Mice, Inbred BALB C Middle Aged Xenograft Model Antitumor Assays
IF 5.168
Human and Animal Cells TE-4(RCB2097) TE-5(RCB1949) TE-8(RCB2098)