title: Proteasome inhibitor MG132 induces thyroid cancer cell apoptosis by modulating the activity of transcription factor FOXO3a.
abstract: Proteasome inhibitors are promising antitumor drugs with preferable cytotoxicity in malignant cells and have exhibited clinical efficiency in several hematologic malignancies. P53-dependent apoptosis has been reported to be a major mechanism underlying. However, apoptosis can also be found in cancer cells with mutant-type p53, suggesting the involvement of p53-independent mechanism. Tumor suppressor forkhead Box O3 is another substrate of proteasomal degradation, which also functions partially through inducing apoptosis. The aim of this study was to explore the effect of proteasome inhibition on the expression and activity of forkhead Box O3 in thyroid cancer cells. Using flow cytometry, western blot, immunofluorescence staining and quantitative RT-PCR assays, we assessed proteasome inhibitor MG132-induced apoptosis in thyroid cancer cells and its effect on the expression and activity of forkhead Box O3. The resulted showed that MG132 induced significant apoptosis, and caused the accumulation of p53 protein in both p53 wild-type and mutant-type thyroid cancer cell lines, whereas the proapoptotic targets of p53 were transcriptionally upregulated only in the p53 wild-type cells. Strikingly, upon MG132 administration, the accumulation and nuclear translocation of transcription factor forkhead Box O3 as well as transcriptional upregulation of its proapoptotic target genes were found in thyroid cancer cells regardless of p53 status. Cell apoptosis was enhanced by ectopic overexpression while attenuated by silencing of forkhead Box O3. Altogether, we demonstrated that proteasome inhibitor MG132 induces thyroid cancer cell apoptosis at least partially through modulating forkhead Box O3 activity.
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, The People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Qiang
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, The People's Republic of China.
authors.forename: Fang
authors.initials: F
authors.lastname: Sui
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, The People's Republic of China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, The People's Republic of China.
authors.forename: Xinru
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, The People's Republic of China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Ren
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, The People's Republic of China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Shao
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, The People's Republic of China.
authors.forename: Jiazhe
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Endocrinology and Metabolism, The First Affiliated Hospital of China Medical University, Shenyang, 110001, The People's Republic of China.
authors.forename: Haixia
authors.initials: H
authors.lastname: Guan
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, The People's Republic of China.|Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, The People's Republic of China.
authors.forename: Bingyin
authors.initials: B
authors.lastname: Shi
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, The People's Republic of China. phou@xjtu.edu.cn.|Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, The People's Republic of China. phou@xjtu.edu.cn.
authors.forename: Peng
authors.initials: P
authors.lastname: Hou
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D000071316:Forkhead Box Protein O3 / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology*; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D015853:Cysteine Proteinase Inhibitors; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D007976:Leupeptins; D061988:Proteasome Inhibitors; D016159:Tumor Suppressor Protein p53; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: Apoptosis; FOXO3a; Proteasome inhibitor MG132; Thyroid cancer