title: Brefeldin A reduces anchorage-independent survival, cancer stem cell potential and migration of MDA-MB-231 human breast cancer cells.
abstract: Cancer stem cells (CSCs) are a subset of cancer cells in tumors or established cancer cell lines that can initiate and sustain the growth of tumors in vivo. Cancer stem cells can be enriched in serum-free, suspended cultures that allow the formation of tumorspheres over several days to weeks. Brefeldin A (BFA) is a mycotoxin that induces endoplasmic reticulum (ER) stress in eukaryotic cells. We found that BFA, at sub-microgram per milliliter concentrations, preferentially induced cell death in MDA-MB-231 suspension cultures (EC50: 0.016 µg/mL) compared to adhesion cultures. BFA also effectively inhibited clonogenic activity and the migration and matrix metalloproteinases-9 (MMP-9) activity of MDA-MB-231 cells. Western blotting analysis indicated that the effects of BFA may be mediated by the down-regulation of breast CSC marker CD44 and anti-apoptotic proteins Bcl-2 and Mcl-1, as well as the reversal of epithelial-mesenchymal transition. Furthermore, BFA also displayed selective cytotoxicity toward suspended MDA-MB-468 cells, and suppressed tumorsphere formation in T47D and MDA-MB-453 cells, suggesting that BFA may be effective against breast cancer cells of various phenotypes.
authors.affiliation: Department of Biomedical Science and Environmental Biology, Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. clcho@faculty.nsysu.edu.tw.
authors.forename: Chao-Neng
authors.initials: CN
authors.lastname: Tseng
authors.affiliation: Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung 80424, Taiwan. m835016@cc.kmu.edu.tw.
authors.forename: Yi-Ren
authors.initials: YR
authors.lastname: Hong
authors.affiliation: Department of Biomedical Science and Environmental Biology, Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. changhw@kmu.edu.tw.
authors.forename: Hsueh-Wei
authors.initials: HW
authors.lastname: Chang
authors.affiliation: Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. raynebox@yahoo.com.tw.
authors.forename: Tsai-Jung
authors.initials: TJ
authors.lastname: Yu
authors.affiliation: Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. kva916@yahoo.com.tw.
authors.forename: Ting-Wei
authors.initials: TW
authors.lastname: Hung
authors.affiliation: Cancer Center and Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan. mifeho@kmu.edu.tw.
authors.forename: Ming-Feng
authors.initials: MF
authors.lastname: Hou
authors.affiliation: Translational Research Center, Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan. 1020005@kmuh.org.tw.
authors.forename: Shyng-Shiou F
authors.initials: SS
authors.lastname: Yuan
authors.affiliation: Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung 80424, Taiwan. clcho@faculty.nsysu.edu.tw.
authors.forename: Chung-Lung
authors.initials: CL
authors.lastname: Cho
authors.affiliation: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. u100022015@cc.kmu.edu.tw.
authors.forename: Chien-Tsung
authors.initials: CT
authors.lastname: Liu
authors.affiliation: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. cchiu@kmu.edu.tw.
authors.forename: Chien-Chih
authors.initials: CC
authors.lastname: Chiu
authors.affiliation: Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. ccjjhh@kmu.edu.tw.
authors.forename: Chih-Jen
authors.initials: CJ
authors.lastname: Huang
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D020126:Brefeldin A / Q000494:pharmacology*; D018929:Cell Culture Techniques / Q000379:methods; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009183:Mycotoxins / Q000494:pharmacology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; C579095:MCL1 protein, human; D009183:Mycotoxins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D020126:Brefeldin A; D020780:Matrix Metalloproteinase 9