title: Hinokitiol inhibits vasculogenic mimicry activity of breast cancer stem/progenitor cells through proteasome-mediated degradation of epidermal growth factor receptor.
abstract: Hinokitiol, alternatively known as β-thujaplicin, is a tropolone-associated natural compound with antimicrobial, anti-inflammatory and antitumor activity. Breast cancer stem/progenitor cells (BCSCs) are a subpopulation of breast cancer cells associated with tumor initiation, chemoresistance and metastatic behavior, and may be enriched by mammosphere cultivation. Previous studies have demonstrated that BCSCs exhibit vasculogenic mimicry (VM) activity via the epidermal growth factor receptor (EGFR) signaling pathway. The present study investigated the anti-VM activity of hinokitiol in BCSCs. At a concentration below the half maximal inhibitory concentration, hinokitiol inhibited VM formation of mammosphere cells derived from two human breast cancer cell lines. Hinokitiol was additionally indicated to downregulate EGFR protein expression in mammosphere-forming BCSCs without affecting the expression of messenger RNA. The protein stability of EGFR in BCSCs was also decreased by hinokitiol. The EGFR protein expression and VM formation capability of hinokitiol-treated BCSCs were restored by co-treatment with MG132, a proteasome inhibitor. In conclusion, the present study indicated that hinokitiol may inhibit the VM activity of BCSCs through stimulating proteasome-mediated EGFR degradation. Hinokitiol may act as an anti-VM agent, and may be useful for the development of novel breast cancer therapeutic agents.
authors.affiliation: Department of Nuclear Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi 60002, Taiwan, R.O.C.; Department of Food Science and Technology, Chia Nan University of Pharmacy & Science, Tainan 717, Taiwan, R.O.C.; Graduate Institute of Medical Sciences, College of Health Sciences, Chang Jung Christian University, Tainan 71101, Taiwan, R.O.C.
authors.forename: Dom-Gene
authors.initials: DG
authors.lastname: Tu
authors.affiliation: School of Biomedical Sciences, College of Medical Science and Technology, Chung Shan Medical University, Taichung 40201, Taiwan, R.O.C.
authors.forename: Yun
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Graduate Institute of Basic Medical Science, School of Medicine, China Medical University, Taichung 40402, Taiwan, R.O.C.; Department of Microbiology, School of Medicine, China Medical University, Taichung 40402, Taiwan, R.O.C.
authors.forename: Che-Hsin
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung 40201, Taiwan, R.O.C.; School of Medical Imaging and Radiological Sciences, Chung Shan Medical University, Taichung 40201, Taiwan, R.O.C.
authors.forename: Yu-Liang
authors.initials: YL
authors.lastname: Kuo
authors.affiliation: Division of Hematology-Oncology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi 60002, Taiwan, R.O.C.
authors.forename: Yin-Che
authors.initials: YC
authors.lastname: Lu
authors.affiliation: Department of Surgery, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi 60002, Taiwan, R.O.C.
authors.forename: Chi-Wen
authors.initials: CW
authors.lastname: Tu
authors.affiliation: School of Biomedical Sciences, College of Medical Science and Technology, Chung Shan Medical University, Taichung 40201, Taiwan, R.O.C.; Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40201, Taiwan, R.O.C.
authors.forename: Wen-Wei
authors.initials: WW
authors.lastname: Chang
keywords: breast cancer stem/progenitor cells; epidermal growth factor receptor; hinokitiol; vasculogenic mimicry