title: CBP-dependent Wnt/β-catenin signaling is crucial in regulation of MDR1 transcription.
abstract: Aberrant expression of the MDR1-encoded P-glycoprotein (P-gp) is often associated with clinical multi-drug resistance (MDR) leading to poor prognosis and failure of chemotherapy. However, the precise and cooperative molecular mechanism responsible for MDR1 transcription and expression in acquired MDR remains elusive. We, herein, demonstrate that Wnt/β-catenin signal pathway is constitutively activated in Doxorubicin-induced MDR cancer cells, in which nuclear β -catenin specifically interacts with the transcriptional coactivator CBP in a MEK(1/2)/ERK(1/2) signal-dependent manner. Specific knockdown of both β-catenin and CBP by RNAi-mediated depletion abrogates MDR1 transcription and expression resulting in a complete reversal of P-gp-dependent efflux function and restoration of sensitivity to the Doxorubincin-induced cytotoxicity. Moreover, following pharmacological disruption of CBP and β - catenin interaction through inhibition of the MEK(1/2)/ERK(1/2) signal by the specific inhibitor PD98059, MDR1 transcription and its encoded P-gp-dependent function are abolished. These findings conclude that the CBP/β-catenin complex is a core component of the MDR1 transcriptional "enhancesome".
authors.forename: Zanxian
authors.initials: Z
authors.lastname: Xia
authors.forename: Mingquan
authors.initials: M
authors.lastname: Guo
authors.forename: Han
authors.initials: H
authors.lastname: Liu
authors.forename: Luwei
authors.initials: L
authors.lastname: Jiang
authors.forename: Qiaoxia
authors.initials: Q
authors.lastname: Li
authors.forename: Jian
authors.initials: J
authors.lastname: Peng
authors.forename: Jia-Da
authors.initials: JD
authors.lastname: Li
authors.forename: Baoen
authors.initials: B
authors.lastname: Shan
authors.forename: Pinghui
authors.initials: P
authors.lastname: Feng
authors.affiliation: Department of Hematology and Oncology, Children's Hospital Los Angeles, University of Southern California, 4650 Sunset Blvd, Los Angeles, CA 90027, USA. hma@chla.usc.edu.
authors.forename: Hong
authors.initials: H
authors.lastname: Ma
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D020014:K562 Cells; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000903:Antibiotics, Antineoplastic; C495270:CTNNB1 protein, human; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D051176:beta Catenin; D004317:Doxorubicin; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases