ABC transporter Pdr5 is required for cantharidin resistance in Saccharomyces cerevisiae.
Biochem Biophys Res Commun
; 553: 141-147, 2021 05 14.
Article
em En
| MEDLINE
| ID: mdl-33770579
ABSTRACT
Cantharidin is a potent anti-cancer drug and is known to exert its cytotoxic effects in several cancer cell lines. Although we have ample knowledge about its mode of action, we still know a little about cantharidin associated drug resistance mechanisms which dictates the efficacy and cytotoxic potential of this drug. In this direction, in the present study we employed Sacharomyces cerevisiae as a model organism and screened mutants of pleiotropic drug resistance network of genes for their susceptibility to cantharidin. We show that growth of pdr1Δ and pdr1Δpdr3Δ was severely reduced in presence of cantharidin whereas that of pdr3Δ remain unaffected when compared to wildtype. Loss of one of the PDR1 target genes PDR5, encoding an ABC membrane efflux pump, rendered the cells hypersensitive whereas overexpression of it conferred resistance. Additionally, cantharidin induced the upregulation of both PDR1 and PDR5 genes. Interestingly, pdr1Δpdr5Δ double deletion mutants were hypersensitive to cantharidin showing a synergistic effect in its cellular detoxification. Furthermore, transcriptional activation of PDR5 post cantharidin treatment was majorly dependent on the presence of Pdr1 and less significantly of Pdr3 transcription factors. Altogether our findings suggest that Pdr1 acts to increase cantharidin resistance by elevating the level of Pdr5 which serves as a major detoxification safeguard under CAN stress.
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MEDLINE
Assunto principal:
Saccharomyces cerevisiae
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Cantaridina
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Transportadores de Cassetes de Ligação de ATP
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Proteínas de Saccharomyces cerevisiae
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Farmacorresistência Fúngica
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article