title: Arsenic trioxide induces programmed cell death through stimulation of ER stress and inhibition of the ubiquitin-proteasome system in human sarcoma cells.
abstract: Sarcoma is a rare form of cancer that differs from the much more common carcinomas because it occurs in a distinct type of tissue. Many patients of sarcoma have poor response to chemotherapy and an increased risk for local recurrence. Arsenic trioxide (ATO) is used to treat certain types of leukemia. Recently, data have revealed that ATO induces sarcoma cell death in several types of solid tumor cell lines. In the present study, we investigated whether ATO induces cancer cell death and elucidated the underlying anti-cancer mechanisms. Our results showed that ATO caused concentration- and time-dependent cell death in human osteosarcoma and fibrosarcoma cells. The types of cell death that were induced by ATO were primarily autophagy and apoptosis. Furthermore, ATO activated p38, JNK and AMPK and inhibited the Akt/mTOR signaling pathways. Specifically, we found that ATO induced endoplasmic reticulum (ER) stress and suppressed proteasome activation in two types of sarcoma cell lines. However, the level of proteasome inhibition in osteosarcoma cells was lower than in fibrosarcoma cells. Thus, we used combined treatment with ATO and a proteasome inhibitor to examine the antitumor activity in fibrosarcoma cells. The data indicated showed that the combination treatment of ATO and MG132 (a proteasome inhibitor) resulted in synergistic cytotoxicity. In a fibrosarcoma xenograft mouse model, the combined treatment significantly reduced tumor progression. Immunohistochemical studies revealed that combined treatment induced autophagy and apoptosis. In summary, our results suggest a potential clinical application of ATO in sarcoma therapy and that combined treatment with a proteasome inhibitor can increase the therapeutic efficacy.
authors.affiliation: Department of Environmental and Occupational Health, National Cheng Kung University, Tainan, Taiwan; Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taiwan; Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Hui-Wen
authors.initials: HW
authors.lastname: Chiu
authors.affiliation: Department of Environmental and Occupational Health, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yin-Chiu
authors.initials: YC
authors.lastname: Tseng
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taiwan.
authors.forename: Yung-Ho
authors.initials: YH
authors.lastname: Hsu
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taiwan; Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yuh-Feng
authors.initials: YF
authors.lastname: Lin
authors.affiliation: Department of Environmental and Occupational Health, National Cheng Kung University, Tainan, Taiwan; Department of Emergency Medicine, Chi-Mei Medical Center, Liouying, Tainan, Taiwan; Department of Emergency Medicine, China Medical University-An Nan Hospital, Tainan, Taiwan.
authors.forename: Ning-Ping
authors.initials: NP
authors.lastname: Foo
authors.affiliation: Department of Environmental and Occupational Health, National Cheng Kung University, Tainan, Taiwan; Department of Occupational and Environmental Medicine, National Cheng Kung University Hospital, Tainan, Taiwan. Electronic address: hrguo@mail.ncku.edu.tw.
authors.forename: How-Ran
authors.initials: HR
authors.lastname: Guo
authors.affiliation: Department of Environmental and Occupational Health, National Cheng Kung University, Tainan, Taiwan; Department of Biomedical Informatics, Asia University, Taichung, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan. Electronic address: yjwang@mail.ncku.edu.tw.
authors.forename: Ying-Jan
authors.initials: YJ
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010087:Oxides / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry* / Q000187:drug effects; D012509:Sarcoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000187:drug effects / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex; D000077237:Arsenic Trioxide
keywords: Apoptosis; Arsenic trioxide; Autophagy; Endoplasmic reticulum stress; Sarcoma; Ubiquitin–proteasome system