MiR-106b~25 cluster regulates multidrug resistance in an ABC transporter-independent manner via downregulation of EP300.

Abstract

MicroRNA (miR)-106b~25 cluster regulates bypass of doxorubicin and γ-radiation induced senescence by downregulation of the E-cadherin transcriptional activator EP300. We asked whether upregulation of miR-106~25 cluster generates cells with a truly multidrug resistant (MDR) phenotype and whether this is due to upregulation of the ATP-binding cassette (ABC) transporter P-glycoprotein. We used minimally transformed mammary epithelial breast cancer cells (MTMECs) in which the miR-106b~25 cluster was experimentally upregulated by lentiviral transfection or in which hairpins targeting either EP300 or E-cadherin mRNAs have been expressed with lentiviruses. We find that overexpression of miR-106b~25 cluster led to the generation of MDR MTMECs (resistant to etoposide, colchicine and paclitaxel). Paclitaxel resistance was also studied after experimental downregulation of EP300 or E-cadherin. However none of these cells overexpressed P-glycoprotein or where able to efflux a fluorescent derivative of paclitaxel, making this phenotype drug-transporter independent. Paclitaxel treatment in MTMECs led to an increase in early apoptotic cells (Annexin V-positive), activation of caspase-9 and increase in the proportion of cells at the G2/M phase of the cell cycle. However, MTMEC overexpressing miR-106b~25 cluster, or with EP300 or E-cadherin downregulated, showed less activation of apoptosis, caspase-9 and caspase-3/-7 activities. Thus, miR-106b~25 cluster controls transporter-independent MDR by apoptosis evasion via downregulation of EP300.

• Authors: Yunhui Hu, Kaiyong Li, Muhammad Asaduzzaman, Raquel Cuella, Hui Shi, Selina Raguz, Raoul Charles Coombes, Yuan Zhou, Ernesto Yagüe
• Journal: Oncology reports (Oncol Rep) Vol. 35 Issue 2 Pg. 1170-8 (Feb 2016) ISSN: 1791-2431 [Electronic] Greece
• PMID: 26573761 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP-Binding Cassette Transporters
• Antineoplastic Agents
• Cadherins
• MIRN106 microRNA, human
• MicroRNAs
• Neoplasm Proteins
• RNA, Neoplasm
• Etoposide
• Doxorubicin
• E1A-Associated p300 Protein
• EP300 protein, human
• Paclitaxel
• Colchicine

Topics

• ATP-Binding Cassette Transporters
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Breast (cytology)
• Cadherins (biosynthesis, genetics)
• Cell Line, Transformed
• Colchicine (pharmacology)
• Down-Regulation
• Doxorubicin (pharmacology)
• Drug Resistance, Multiple (genetics)
• Drug Resistance, Neoplasm (genetics)
• E1A-Associated p300 Protein (biosynthesis, genetics)
• Epithelial Cells (drug effects, radiation effects)
• Etoposide (pharmacology)
• Gamma Rays
• Humans
• MicroRNAs (genetics)
• Multigene Family
• Neoplasm Proteins (genetics, physiology)
• Paclitaxel (pharmacology)
• Phenotype
• RNA, Neoplasm (genetics)
• Transduction, Genetic
• Tumor Stem Cell Assay