Abstract
BackgroundEsophageal cancer is the sixth leading cause of cancer-related mortality worldwide, which is partially due to limited progress of therapy. Apatinib, an inhibitor of VEGFR2, has a promising antitumor effect on malignancies. However, the underlying mechanism of its antitumor effect on esophageal cancer remains poorly understood.Materials and methodsEighteen pairs of frozen esophageal cancer and their para-cancer samples and 25 paraffin specimens from advanced esophageal cancer patients treated with cisplatin-based regimen were collected. The effects of apatinib on cell growth, cell apoptosis, cell cycle and invasion/migration of esophageal cancer cells were assessed. Bioinformatics, luciferase reporter, immunoprecipitation and immunofluorescence assays were conducted for mechanic investigation. Quantitative RT-PCR, western blotting and immunohistochemistry were used to measure the expression of functional genes. Xenograft tumor growth of mice was performed.ResultsWe found that VEGFR2 was highly expressed in esophageal cancer and associated with poor efficacy of cisplatin-based treatment. Apatinib displayed profound actions against tumor cell growth of human esophageal cancer via promoting cell apoptosis and cell cycle arrest. Also, apatinib displayed the inhibitory effects on cell migration and invasion. Moreover, apatinib strongly suppressed the growth of esophageal cancer xenografts in mice. The effects of apatinib on esophageal cancer were partially dependent on its block of the VEGFR2/Akt/β-catenin pathway. Specifically, apatinib induced the degradation of β-catenin and decreased its transcriptional activity through Akt/GSK-3β repression. Further in vitro and in vivo studies revealed that low dose apatinib had a synergistic antitumor effect with cisplatin on esophageal cancer.ConclusionOur study indicates that apatinib suppresses tumor progression and enhances cisplatin sensitivity in esophageal cancer by deactivating the Akt/β-catenin pathway. These findings provide a theoretical foundation for using apatinib as an effective therapeutic drug for esophageal cancer.
Highlights
Esophageal cancer is the sixth leading cause of cancer-related mortality worldwide, which is partially due to limited progress of therapy
Our study indicates that apatinib suppresses tumor progression and enhances cisplatin sensitivity in esophageal cancer by deactivating the Akt/β-catenin pathway
We found that apatinib inhibited the growth of esophageal cancer and sensitized tumors to cisplatin by deactivating the Akt/β-catenin pathway, which provided a theoretical basis of apatinib as a potential candidate for the treatment of esophageal cancer
Summary
Esophageal cancer is the sixth leading cause of cancer-related mortality worldwide, which is partially due to limited progress of therapy. An inhibitor of VEGFR2, has a promising antitumor effect on malignancies. The underlying mechanism of its antitumor effect on esophageal cancer remains poorly understood. Esophageal cancer is the ninth most common malignancy with rapidly increasing incidence and the sixth leading cause of cancer-related death worldwide [1]. With the tolerable side effects and improved survival benefits, apatinib has been approved by the China Food and Drug Administration for advanced gastric cancer in third-line or later treatment [9]. Few clinical retrospective studies have preliminarily suggested that apatinib alone or in combination with chemotherapy is efficacious for advanced esophageal cancer as a secondline or later treatment [16, 17]. The possible function and mechanism of apatinib in the treatment of esophageal cancer is still poorly understood
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