title: Combining radiation with autophagy inhibition enhances suppression of tumor growth and angiogenesis in esophageal cancer.
abstract: Radiotherapy is an effective treatment for esophageal cancer; however, tumor resistance to radiation remains a major biological problem. The present study aimed to investigate whether inhibition of autophagy may decrease overall tumor resistance to radiation. The effects of the autophagy inhibitor 3-methyladenine (3-MA) on radiosensitivity were tested in the EC9706 human esophageal squamous cell carcinoma cell line by colony formation assay. Furthermore, the synergistic cytotoxic effects of 3-MA and radiation were assessed in a tumor xenograft model in nude mice. Mechanistic studies were performed using flow cytometry, immunohistochemistry and western blot analysis. The results of the present study demonstrated that radiation induced an accumulation of autophagosomes and 3-MA effectively inhibited radiation-induced autophagy. Inhibition of autophagy was shown to significantly increase the radiosensitivity of the tumors in vitro and in vivo. The enhancement ratio of sensitization in EC9706 cells was 1.76 when the cells were treated with 10 mM 3-MA, alongside ionizing radiation. In addition, autophagy inhibition increased apoptosis and reduced tumor cell proliferation. The combination of radiation and autophagy inhibition resulted in a significant reduction in tumor volume and vasculature in the murine model. The present study demonstrated in vitro and in vivo that radiation-induced autophagy has a protective effect against cell death, and inhibition of autophagy is able to enhance the radiosensitivity of esophageal squamous cell carcinoma.
authors.affiliation: Department of Radiation Oncology, Zhengzhou University Affiliated Cancer Hospital, Henan Cancer Hospital, Zhengzhou, Henan 450008, P.R. China.
authors.forename: Yongshun
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pathology, Zhengzhou University Affiliated Cancer Hospital, Henan Cancer Hospital, Zhengzhou, Henan 450008, P.R. China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Radiation Oncology, Zhengzhou University Affiliated Cancer Hospital, Henan Cancer Hospital, Zhengzhou, Henan 450008, P.R. China.
authors.forename: Leiming
authors.initials: L
authors.lastname: Guo
authors.affiliation: Department of Radiation Oncology, Zhengzhou University Affiliated Cancer Hospital, Henan Cancer Hospital, Zhengzhou, Henan 450008, P.R. China.
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Radiation Oncology, Zhengzhou University Affiliated Cancer Hospital, Henan Cancer Hospital, Zhengzhou, Henan 450008, P.R. China.
authors.forename: Chunyu
authors.initials: C
authors.lastname: He
authors.affiliation: Department of Radiation Oncology, Zhengzhou People's Hospital, Zhengzhou, Henan 450053, P.R. China.
authors.forename: Song
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Zhengzhou University Affiliated Zhengzhou Central Hospital, Zhengzhou, Henan 450003, P.R. China.
authors.forename: Yanjing
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Department of Radiation Oncology, Zhengzhou University Affiliated Cancer Hospital, Henan Cancer Hospital, Zhengzhou, Henan 450008, P.R. China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Radiation Oncology, Zhengzhou University Affiliated Cancer Hospital, Henan Cancer Hospital, Zhengzhou, Henan 450008, P.R. China.
authors.forename: Daxuan
authors.initials: D
authors.lastname: Hao
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects / Q000528:radiation effects*; D000071186:Beclin-1; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D004938:Esophageal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D000077277:Esophageal Squamous Cell Carcinoma; D004947:Esophagus / Q000098:blood supply; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009389:Neovascularization, Pathologic; D011836:Radiation Tolerance / Q000187:drug effects; D011839:Radiation, Ionizing; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C477012:MAP1LC3A protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D042461:Vascular Endothelial Growth Factor A; C025946:3-methyladenine; D000225:Adenine