title: Dietary compound isoliquiritigenin targets GRP78 to chemosensitize breast cancer stem cells via β-catenin/ABCG2 signaling.
abstract: Accumulating evidence suggests that β-catenin signaling in breast cancer stem cells (CSCs) is closely correlated to chemoresistance and adenosine triphosphate (ATP)-binding cassette subfamily G2 (ABCG2) expression. Targeting the aberrant β-catenin signaling in CSCs has become a promising strategy to improve chemosensitivity in cancer treatment. In a pilot screening study, we found that the natural compound isoliquiritigenin (ISL) blocked β-catenin transcription activity with the highest inhibition ratio. Here, we investigated the chemosensitizing effects of ISL on breast CSCs and the underlying mechanisms regulating the β-catenin pathway. ISL could have synergistic effects with chemotherapeutic drugs to inhibit breast cancer cell proliferation and colony formation. In addition, ISL could significantly limit the side population and CSC ratios in breast cancer cells, accompanied by inhibited self-renewal and multidifferentiation abilities. A mechanistic study revealed that ISL could inhibit β-catenin/ABCG2 signaling by activating the proteasome degradation pathway. The drug affinity responsive target stability strategy further identified GRP78 as the direct target of ISL. Subsequent molecular docking analysis and functional studies demonstrated that ISL could dock into the ATP domain of GRP78 and thereby inhibit its ATPase activity, resulting in its dissociation from β-catenin. An in vivo study also suggested that ISL could chemosensitize breast CSCs via the GRP78/β-catenin/ABCG2 pathway, with little toxicity in normal tissues and mammary stem cells. Taken together, the data from this study not only suggest ISL as a natural candidate to enhance breast CSC chemosensitivity but also highlight the significance of GRP78 in mediating cancer drug resistance and β-catenin signaling in CSCs.
authors.affiliation: School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Estates Building, 10 Sassoon Road, Hong Kong 00852, China.
authors.forename: Neng
authors.initials: N
authors.lastname: Wang
authors.affiliation: School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Estates Building, 10 Sassoon Road, Hong Kong 00852, China, Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical Medical Collage, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, China and.
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Pharmacy College,Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610075, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Peng
authors.affiliation: School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Estates Building, 10 Sassoon Road, Hong Kong 00852, China.
authors.forename: Jieshu
authors.initials: J
authors.lastname: You
authors.affiliation: School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Estates Building, 10 Sassoon Road, Hong Kong 00852, China.
authors.forename: Jiangang
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical Medical Collage, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, China and.
authors.forename: Shouwei
authors.initials: S
authors.lastname: Han
authors.affiliation: School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Estates Building, 10 Sassoon Road, Hong Kong 00852, China, jpjpchen@yahoo.com.
authors.forename: Jianping
authors.initials: J
authors.lastname: Chen
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis*; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation; D047188:Chalcones / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D062105:Molecular Docking Simulation; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D047188:Chalcones; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D009363:Neoplasm Proteins; D051176:beta Catenin; C040920:isoliquiritigenin