title: Enhanced autophagy reveals vulnerability of P-gp mediated epirubicin resistance in triple negative breast cancer cells.
abstract: Epirubicin (EPI) is widely used for triple negative breast cancer (TNBC), but a substantial number of patients develop EPI resistance that is associated with poor outcome. The underlying mechanism for EPI resistance remains poorly understood. We have developed and characterized an EPI-resistant (EPI-R) cell line from parental MDA-MB-231 cells. These EPI-R cells reached stable growth in the medium containing 8 μg/ml of EPI. They overexpressed P-glycoprotein (P-gp) and contained numerous autophagic vacuoles. The suppression of P-gp overexpression and/or autophagy restored the sensitivity of these EPI-R cells to EPI. We further show that autophagy conferred resistance to EPI on MDA cells by blocking the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-mediated pro-apoptotic signals. Together, these results reveal a synergistic role of P-gp, autophagy, and NF-κB pathways in the development of EPI resistance in TNBC cells. They also suggest that blocking the P-gp overexpression and autophagy may be an effective means of reducing EPI resistance.
authors.affiliation: Institute of Integrated Traditional Chinese and Western Medicine, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, Gansu, China. zhanglh14@lzu.edu.cn.|Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, 199 West Donggang Road, Lanzhou, 730000, Gansu, China. zhanglh14@lzu.edu.cn.
authors.forename: Li-han
authors.initials: LH
authors.lastname: Zhang
authors.affiliation: Institute of Integrated Traditional Chinese and Western Medicine, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, Gansu, China. yangaijun999@126.com.|Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, 199 West Donggang Road, Lanzhou, 730000, Gansu, China. yangaijun999@126.com.
authors.forename: Ai-jun
authors.initials: AJ
authors.lastname: Yang
authors.affiliation: Institute of Integrated Traditional Chinese and Western Medicine, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, Gansu, China. wmin@lzu.edu.cn.|Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, 199 West Donggang Road, Lanzhou, 730000, Gansu, China. wmin@lzu.edu.cn.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, 199 West Donggang Road, Lanzhou, 730000, Gansu, China. blliuwei@163.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, 199 West Donggang Road, Lanzhou, 730000, Gansu, China. wangcylz@126.com.
authors.forename: Chen-yu
authors.initials: CY
authors.lastname: Wang
authors.affiliation: Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, 199 West Donggang Road, Lanzhou, 730000, Gansu, China. xiexf08@163.com.
authors.forename: Xiao-feng
authors.initials: XF
authors.lastname: Xie
authors.affiliation: Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, 199 West Donggang Road, Lanzhou, 730000, Gansu, China. chenxu19880816@126.com.
authors.forename: Xu
authors.initials: X
authors.lastname: Chen
authors.affiliation: BloodWorks Northwest Research Institute, Seattle, WA, 98102, USA. jfdong@psbc.org.|Division of Hematology, Department of Medicine, University of Washington, School of Medicine, Seattle, WA, 98102, USA. jfdong@psbc.org.
authors.forename: Jing-fei
authors.initials: JF
authors.lastname: Dong
authors.affiliation: Institute of Integrated Traditional Chinese and Western Medicine, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, Gansu, China. limin@lzu.edu.cn.|Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, 199 West Donggang Road, Lanzhou, 730000, Gansu, China. limin@lzu.edu.cn.|Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Lanzhou University, Lanzhou, 730000, Gansu, China. limin@lzu.edu.cn.
authors.forename: Min
authors.initials: M
authors.lastname: Li
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis / Q000235:genetics; D017209:Apoptosis; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1 / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D015251:Epirubicin / Q000494:pharmacology*; D005260:Female; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; C491997:BECN1 protein, human; D000071186:Beclin-1; D016328:NF-kappa B; D034741:RNA, Small Interfering; D015251:Epirubicin
keywords: Autophagy; Chemotherapy resistance; Epirubicin; NF-κB; P-gp; Triple negative breast cancer