title: HOXB4 knockdown reverses multidrug resistance of human myelogenous leukemia K562/ADM cells by downregulating P-gp, MRP1 and BCRP expression via PI3K/Akt signaling pathway.
abstract: Multidrug resistance (MDR) plays a pivotal role in human chronic myelogenous leukemia (CML) chemotherapy failure. MDR is mainly associated with the overexpression of drug efflux transporters of the ATP-binding cassette (ABC) proteins. Phosphoinositide 3-kinase (PI3K)/Akt signaling cascade is involved in the MDR phenotype and is correlated with multidrug resistance 1 (MDR1)/P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1) and breast cancer resistance protein (BCRP) expression in many human malignancies. Homeobox (HOX) B4, a member of the HOX gene family, has been reported to be correlated with occurrence, development, poor prognosis and drug resistance of human leukemia. In the present study, HOXB4 expression was analyzed in K562 cell line and its MDR subline K562/ADM. Compared with K562 cells, drug-resistant K562/ADM cells demonstrated evidently higher HOXB4 expression. In addition, we firstly investigated the reversal effect of HOXB4 deletion on K562/ADM cells and the underlying mechanism. The Cell Counting kit-8 (CCK-8) and flow cytometry assays showed that knockdown of HOXB4 enhanced chemosensitivity and decreased drug efflux in K562/ADM cells. Moreover, HOXB4 knockout led to downregulation of P-gp, MRP1 and BCRP expression and PI3K/Akt signaling activity, suggesting that repression of HOXB4 might be a key point to reverse MDR of K562/ADM cells.
authors: Department of Pediatrics, The Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong 256603, P.R. China.
authors: Hong
authors: H
authors: Wang
authors: Department of Pediatrics, The Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong 256603, P.R. China.
authors: Xiu-Hong
authors: XH
authors: Jia
authors: Department of Pediatrics, The Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong 256603, P.R. China.
authors: Jie-Ru
authors: JR
authors: Chen
authors: Department of Pediatrics, The Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong 256603, P.R. China.
authors: Ying-Jie
authors: YJ
authors: Yi
authors: Department of Pediatrics, The Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong 256603, P.R. China.
authors: Jian-Yong
authors: JY
authors: Wang
authors: Department of Biochemistry and Molecular Biology, Key Laboratory of Tumour Molecular Biology, Binzhou Medical University, Yantai, Shandong 264003, P.R. China.
authors: You-Jie
authors: YJ
authors: Li
authors: Department of Biochemistry and Molecular Biology, Key Laboratory of Tumour Molecular Biology, Binzhou Medical University, Yantai, Shandong 264003, P.R. China.
authors: Shu-Yang
authors: SY
authors: Xie
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000096:biosynthesis / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003561:Cytarabine / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005047:Etoposide / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000235:genetics; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*; D014751:Vindesine / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D000970:Antineoplastic Agents; D003561:Cytarabine; D004317:Doxorubicin; D005047:Etoposide; D018398:Homeodomain Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D014751:Vindesine; C116614:ABCG2 protein, human; C090460:HOXB4 protein, human; C421109:multidrug resistance-associated protein 1