title: Micheliolide overcomes KLF4-mediated cisplatin resistance in breast cancer cells by downregulating glutathione.
abstract: Micheliolide (MCL) is a promising novel compound with broad-spectrum anticancer activity. However, little is known regarding its action and mechanism in breast cancer. To explore the potential therapeutic application of MCL as a chemosensitivity modulator, this study investigated the effects of MCL on cisplatin sensitivity in breast cancer and the underlying mechanisms. In the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cytotoxicity assay and a xenograft tumor model, MCL enhanced the cisplatin sensitivity of the breast cancer cell line MCF-7 both in vitro and in vivo. Treatment of MCF-7 cells with low-dose cisplatin (10 µM) was sufficient to enrich the proportion of ALDH(+) cells and upregulate Krüppel-like factor 4 (KLF4) expression. The results obtained from knockdown and overexpression experiments demonstrate that KLF4 is both necessary and sufficient to induce a cisplatin resistance phenotype in breast cancer cells. Furthermore, the glutathione (GSH) content was elevated in MCF-7 cells after overexpression of KLF4. KLF4-mediated resistance to cisplatin was found to be abrogated by treatment with buthionine sulfoximine, an inhibitor of GSH synthesis. MCL induced GSH depletion and severe cell death in KLF4-overexpressing MCF-7 cells following exposure to cisplatin. Therefore, these results suggest that MCL-mediated direct depletion of GSH represents a major mechanism in reversing KLF4-induced cisplatin resistance in MCF-7 cells.
authors.affiliation: Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Tianjin, People's Republic of China.
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Department of Colorectal Surgery, Tianjin Union Medicine Center, Tianjin, People's Republic of China.
authors.forename: Chunze
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Tianjin, People's Republic of China.
authors.forename: Liyan
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Oncology, Anhui Provincial Tumor Hospital, Hefei, People's Republic of China.
authors.forename: Huijun
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Tianjin, People's Republic of China.
authors.forename: Yehui
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Tianjin, People's Republic of China.
authors.forename: Zhongsheng
authors.initials: Z
authors.lastname: Tong
keywords: KLF4; Micheliolide; breast cancer; cisplatin resistance; glutathione