Dataset Information

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

ABSTRACT: 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a topic that is not usually addressed is the mechanism underlying the loss of CDR once the challenge to these cells is withdrawn.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.

SUBMITTER: Gomes BC

PROVIDER: S-EPMC7215654 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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

Gomes Bruno C BC Honrado Mónica M Armada Ana A Viveiros Miguel M Rueff José J Rodrigues António S AS

International journal of molecular sciences 20200423 8

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a topic that is not usually addressed is the mechanism underlying the loss of CDR once the challenge to these cells is withdrawn.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 withdra ...[more]

PMID: 32340269

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Project description:ATP-binding cassette (ABC) drug efflux transporters could contribute to low intracellular concentrations of antiretroviral drugs in HIV-1 cell reservoirs and sanctuary sites. Furthermore, the functional expression of these transporters could be induced in activated T-cells. Therefore, we investigated the expression of ABC drug efflux transporters in human T-cells exposed to an HIV pseudotype virus (pHIVNL4-3), and further examined the potential involvement of the mammalian target of rapamycin (mTOR) signaling pathway in regulating their expression following exposure to pHIVNL4-3. Additionally, we investigated the contribution of the drug efflux transporters to the inflammatory response following pHIVNL4-3-induced T-cell activation. Human peripheral blood mononuclear cells (PBMCs) were exposed to HIV-1 envelope glycoprotein gp120IIIB, pHIVNL4-3 and/or mTOR inhibitors. The expression of ABC transporters, T-cell activation marker CD69, mTOR and pHIVNL4-3 was assessed in CD4+ T-cells by Flow cytometry. mRNA and protein levels of proinflammatory cytokines (IL6, TNFα and INFγ) were examined in PBMCs by qPCR and ELISA analyses, respectively, following exposure to pHIVNL4-3 with or without inhibitors of mTOR or ABC transporters. The expression of ABC transporters (P-glycoprotein, breast cancer resistance protein and multi-drug resistance associated protein-1) was significantly increased in CD4+ T-cells exposed to pHIVNL4-3. Treatment with mTOR inhibitors attenuated pHIVNL4-3-induced transporter expression, as well as mRNA and protein levels of IL6, TNFα and INFγ. Additionally, inhibition of P-gp or MRP1 activity resulted in lower concentrations of proinflammatory cytokines in supernatants of PBMC exposed to pHIVNL4-3. Herein we present novel data demonstrating that upregulation of ABC drug efflux transporters could involve the mTOR signaling pathway in CD4+ T-cells exposed to an HIV pseudotype. These transporters could limit antiretroviral drug penetration in HIV target T-cells. Furthermore, ABC transporters could potentially contribute to HIV-associated proinflammatory cytokine secretion.

Dataset Information

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

Publications

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

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