title: Ovatodiolide Inhibits Breast Cancer Stem/Progenitor Cells through SMURF2-Mediated Downregulation of Hsp27.
abstract: Cancer stem/progenitor cells (CSCs) are a subpopulation of cancer cells involved in tumor initiation, resistance to therapy and metastasis. Targeting CSCs has been considered as the key for successful cancer therapy. Ovatodiolide (Ova) is a macrocyclic diterpenoid compound isolated from Anisomeles indica (L.) Kuntze with anti-cancer activity. Here we used two human breast cancer cell lines (AS-B145 and BT-474) to examine the effect of Ova on breast CSCs. We first discovered that Ova displayed an anti-proliferation activity in these two breast cancer cells. Ova also inhibited the self-renewal capability of breast CSCs (BCSCs) which was determined by mammosphere assay. Ova dose-dependently downregulated the expression of stemness genes, octamer-binding transcription factor 4 (Oct4) and Nanog, as well as heat shock protein 27 (Hsp27), but upregulated SMAD ubiquitin regulatory factor 2 (SMURF2) in mammosphere cells derived from AS-B145 or BT-474. Overexpression of Hsp27 or knockdown of SMURF2 in AS-B145 cells diminished the therapeutic effect of ovatodiolide in the suppression of mammosphere formation. In summary, our data reveal that Ova displays an anti-CSC activity through SMURF2-mediated downregulation of Hsp27. Ova could be further developed as an anti-CSC agent in the treatment of breast cancer.
authors.affiliation: Department of Anesthesiology, Changhua Christian Hospital, Changhua 500, Taiwan. 97343@cch.org.tw.
authors.forename: Kuan-Ta
authors.initials: KT
authors.lastname: Lu
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Changhua Christian Hospital, Changhua 500, Taiwan. 156283@cch.org.tw.|School of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. 156283@cch.org.tw.|Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung 402, Taiwan. 156283@cch.org.tw.
authors.forename: Bing-Yen
authors.initials: BY
authors.lastname: Wang
authors.affiliation: School of Biomedical Sciences, Chung Shan Medical University, Taichung 40201, Taiwan. zx82704@yahoo.com.tw.
authors.forename: Wan-Yu
authors.initials: WY
authors.lastname: Chi
authors.affiliation: School of Biomedical Sciences, Chung Shan Medical University, Taichung 40201, Taiwan. swan1204@hotmail.com.|Institute of Microbiology &amp; Immunology, Chung Shan Medical University, Taichung 40201, Taiwan. swan1204@hotmail.com.
authors.forename: Ju
authors.initials: J
authors.lastname: Chang-Chien
authors.affiliation: School of Biomedical Sciences, Chung Shan Medical University, Taichung 40201, Taiwan. jiannjou@csmu.edu.tw.|Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40201, Taiwan. jiannjou@csmu.edu.tw.
authors.forename: Jiann-Jou
authors.initials: JJ
authors.lastname: Yang
authors.affiliation: Institute of Anatomy and Cell Biology, School of Medicine, National Yang Ming University, Taipei 11221, Taiwan. incubator.lee@ym.edu.tw.
authors.forename: Hsueh-Te
authors.initials: HT
authors.lastname: Lee
authors.affiliation: Center for General Education, National Taitung University, Taitung 95092, Taiwan. tzengym@gmail.com.|Department of Appiled Chemistry, Chaoyang University of Technology, Taichung 41349, Taiwan. tzengym@gmail.com.
authors.forename: Yew-Min
authors.initials: YM
authors.lastname: Tzeng
authors.affiliation: School of Biomedical Sciences, Chung Shan Medical University, Taichung 40201, Taiwan. changww@csmu.edu.tw.|Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40201, Taiwan. changww@csmu.edu.tw.
authors.forename: Wen-Wei
authors.initials: WW
authors.lastname: Chang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004224:Diterpenes / Q000494:pharmacology*; D015536:Down-Regulation; D005260:Female; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics*; D006360:Heat-Shock Proteins; D006801:Humans; D018832:Molecular Chaperones; D000071317:Nanog Homeobox Protein / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D050814:Octamer Transcription Factor-3 / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D004224:Diterpenes; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C432447:ovatodiolide; C471641:SMURF2 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: Hsp27; SMURF2; cancer stem/progenitor cells; ovatodiolide