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

• Published in: International journal of oncology Vol. 49; no. 6; pp. 2529 - 2537
• Main Authors: Wang, Hong, Jia, Xiu-Hong, Chen, Jie-Ru, Yi, Ying-Jie, Wang, Jian-Yong, Li, You-Jie, Xie, Shu-Yang
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01.12.2016; Spandidos Publications; Spandidos Publications UK Ltd
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis; ATP Binding Cassette Transporter, Sub-Family G, Member 2 - biosynthesis; ATP Binding Cassette Transporter, Sub-Family G, Member 2 - genetics; ATP-Binding Cassette, Sub-Family B, Member 1 - biosynthesis; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; BCRP; Biological Transport - drug effects; Breast cancer; Cancer therapies; Care and treatment; Cell cycle; Cell Line, Tumor; Cell Proliferation - drug effects; Cellular signal transduction; Chemotherapy; Chromosomes; Chronic myeloid leukemia; Cytarabine - pharmacology; Cytotoxicity; Development and progression; Doxorubicin - pharmacology; Drug resistance; Drug Resistance, Multiple - genetics; Drug Resistance, Neoplasm - genetics; Etoposide - pharmacology; Genes; Genetic aspects; Genotype & phenotype; Health aspects; Homeodomain Proteins - genetics; HOXB4; Humans; Kinases; Laboratories; Leukemia; Leukemia, Myeloid - drug therapy; Leukemia, Myeloid - genetics; Medical prognosis; MRP1; multidrug resistance; Multidrug Resistance-Associated Proteins - biosynthesis; Multidrug Resistance-Associated Proteins - genetics; Multidrug resistant organisms; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; P-glycoprotein; phosphoinositide 3-kinase; Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; RNA, Small Interfering - genetics; Transcription factors; Transcription Factors - genetics; Vindesine - pharmacology
• ISSN: 1019-6439; 1791-2423
• DOI: 10.3892/ijo.2016.3738

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.