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Open AccessArticle

ABC Efflux Transporters and the Circuitry of miRNAs: Kinetics of Expression in Cancer Drug Resistance

1
Centre for Toxicogenomics and Human Health; Genetics, Oncology and Human Toxicology, NOVA Medical School, Universidade NOVA de Lisboa, Rua Câmara Pestana 6, 1150-008 Lisbon, Portugal
2
Global Health and Tropical Medicine, Instituto de Higiene e Medicina Tropical, Universidade NOVA de Lisboa, Rua da Junqueira 100, 1349-008 Lisbon, Portugal
*
Author to whom correspondence should be addressed.
These authors contributed equally to this manuscript.
Int. J. Mol. Sci. 2020, 21(8), 2985; https://doi.org/10.3390/ijms21082985
Received: 30 March 2020 / Revised: 18 April 2020 / Accepted: 22 April 2020 / Published: 23 April 2020
Cancer drug resistance (CDR) is a major problem in therapeutic failure. Over 90% of patients with metastatic cancer present CDR. Several mechanisms underlie CDR, including the increased expression of efflux ABC transporters and epigenetic phenomena. Nevertheless, a topic that is not usually addressed is the mechanism underlying the loss of CDR once the challenge to these cells is withdrawn. A KCR cell line (doxorubicin-resistant, expressing ABCB1) was used to induce loss of resistance by withdrawing doxorubicin in culture medium. ABCB1 activity was analysed by fluorescence microscopy and flow cytometry through substrate (DiOC2) retention assays. The expression of 1008 microRNAs was assessed before and after doxorubicin withdrawal. After 16 weeks of doxorubicin withdrawal, a decrease of ABCB1 activity and expression occurred. Moreover, we determined a signature of 23 microRNAs, 13 underexpressed and 10 overexpressed, as a tool to assess loss of resistance. Through pathway enrichment analysis, “Pathways in cancer”, “Proteoglycans in cancer” and “ECM-receptor interaction” were identified as relevant in the loss of CDR. Taken together, the data reinforce the assumption that ABCB1 plays a major role in the kinetics of CDR, and their levels of expression are in the dependence of the circuitry of cell miRNAs. View Full-Text
Keywords: cancer drug resistance; microRNAs; gene regulation; ABC drug transporters; ABCB1; MDR1; doxorubicin cancer drug resistance; microRNAs; gene regulation; ABC drug transporters; ABCB1; MDR1; doxorubicin
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Gomes, B.C.; Honrado, M.; Armada, A.; Viveiros, M.; Rueff, J.; Rodrigues, A.S. ABC Efflux Transporters and the Circuitry of miRNAs: Kinetics of Expression in Cancer Drug Resistance. Int. J. Mol. Sci. 2020, 21, 2985.

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