In silico identification of thiostrepton as an inhibitor of cancer stem cell growth and an enhancer for chemotherapy in non–small-cell lung cancer
Journal
Journal of Cellular and Molecular Medicine
Journal Volume
23
Journal Issue
12
Pages
8184-8195
Date Issued
2019
Author(s)
Huang T.-H.
Wu A.T.H.
Cheng T.-S.
Lin K.-T.
Lai C.-J.
Hsieh H.-W.
Chang P.M.-H.
Wu C.-W.
Huang C.-Y.F.
Abstract
Cancer stem cells (CSCs) play an important role in cancer treatment resistance and disease progression. Identifying an effective anti-CSC agent may lead to improved disease control. We used CSC-associated gene signatures to identify drug candidates that may inhibit CSC growth by reversing the CSC gene signature. Thiostrepton, a natural cyclic oligopeptide antibiotic, was the top-ranked candidate. In non–small-cell lung cancer (NSCLC) cells, thiostrepton inhibited CSC growth in vitro and reduced protein expression of cancer stemness markers, including CD133, Nanog and Oct4A. In addition, metastasis-associated Src tyrosine kinase signalling, cell migration and epithelial-to-mesenchymal transition (EMT) were all inhibited by thiostrepton. Mechanistically, thiostrepton treatment led to elevated levels of tumour suppressor miR-98. Thiostrepton combined with gemcitabine synergistically suppressed NSCLC cell growth and induced apoptosis. The inhibition of NSCLC tumours and CSC growth by thiostrepton was also demonstrated in vivo. Our findings indicate that thiostrepton, an established drug identified in silico, is an inhibitor of CSC growth and a potential enhancer of chemotherapy in NSCLC. ? 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
SDGs
Other Subjects
aldehyde dehydrogenase; CD133 antigen; cisplatin; CL141 antigen; forkhead box protein M1; gefitinib; gemcitabine; Hermes antigen; microRNA; microRNA 98; nerve cell adhesion molecule; octamer transcription factor 4; octamer transcription factor 4A; pemetrexed; protein kinase B; protein kinase p60; salinomycin; thiostrepton; transcription factor NANOG; transcription factor Slug; transcription factor Snail; transcription factor Sox2; unclassified drug; uvomorulin; vimentin; antiinfective agent; microRNA; MIRN98 microRNA-98, rat; thiostrepton; transcription factor NANOG; animal experiment; animal model; apoptosis; Article; cancer chemotherapy; cancer inhibition; cancer stem cell; cell migration assay; colony formation; computer model; controlled study; cytotoxicity assay; down regulation; drug mechanism; epithelial mesenchymal transition; female; flow cytometry; gene expression profiling; human; human cell; ligation mediated polymerase chain reaction; microarray analysis; mouse; non small cell lung cancer; nonhuman; priority journal; protein expression; real time polymerase chain reaction; scoring system; signal transduction; upregulation; Western blotting; A-549 cell line; animal; cancer stem cell; cell motion; cell proliferation; cell survival; computer simulation; drug effect; drug screening; gene expression regulation; genetics; lung tumor; metabolism; non small cell lung cancer; nonobese diabetic mouse; pathology; procedures; SCID mouse; tumor cell line; A549 Cells; Animals; Anti-Bacterial Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Computer Simulation; Epithelial-Mesenchymal Transition; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Mice, Inbred NOD; Mice, SCID; MicroRNAs; Nanog Homeobox Protein; Neoplastic Stem Cells; Signal Transduction; Thiostrepton; Xenograft Model Antitumor Assays
Publisher
Blackwell Publishing Inc.
Type
journal article