Abstract
Persistent organic pollutants (POPs) may alter tumor cells phenotype, possibly increasing malignancy, but there is a lack of studies investigating the mechanisms by which POPs may affect tumor cells. The ATP-Binding Cassette (ABC) transporter proteins are a widely studied component of drug resistance and tumor progression. We hypothesized that the levels of BDE-209 and TCDD detected in human serum can modulate the gene expression or activity of ATP-binding cassette (ABC) transporters in murine melanoma (B16-F1) cells. In this study, we observed an upregulation of the ABCB1 and ABCC4 (24 h) genes followed by an increased protein activity after BDE-209 15 day-exposure. We also observed that cells exposed to TCDD showed an upregulation of ABCB5, ABCC1 and ABCC4 genes (24 h) and change of protein activity after 15 days of exposure. These findings suggest that BDE-209 and TCDD can regulate the phenotype of B16-F1 cells by interfering with the expression and activity of ATP-binding cassette (ABC) transporters. This investigation revealed that environmental pollutants might intervene and modify cells’ resistance to chemotherapy and cancer prognosis.
Highlights
Melanoma originates from the transformation of melanocytes and leads to high mortality due to its aggressiveness and a low response to treatments [1, 2]
We observed that cells exposed to TCDD showed an upregulation of ABCB5, ABCC1 and ABCC4 genes (24 h) and change of protein activity after 15 days of exposure. These findings suggest that BDE-209 and TCDD can regulate the phenotype of B16-F1 cells by interfering with the expression and activity of ATP-binding cassette (ABC) transporters
We investigated the role of TCDD and BDE-209 in the modulation of ABC transporter proteins in murine melanoma cells (B16-F1) after acute and chronic exposure at concentrations previously found in human plasma
Summary
Melanoma originates from the transformation of melanocytes and leads to high mortality due to its aggressiveness and a low response to treatments [1, 2]. The role of ABC system is to direct the flux of different substrates through membranes, including anticancer drugs and environmental xenobiotics. These proteins are structurally grouped into two transmembrane regions (TMDs) that bind and translocate different substrates, and two nucleotide ATP binding domains (NBDs) [5]. Two subfamilies of ABC transporters are important in melanoma: ABCB and ABCC. The genes ABCB1, ABCB5, ABCC1, ABCC2 and ABCC4 code for PGP1, denominated MDR1, while PGP5 (MDR5), MRP1, MRP2 and MRP4 proteins confer resistance to multiple drugs in normal and melanoma cells [6, 7]. The ABC transport proteins were suggested to be involved in the initiation and progression of tumors [8]
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