Differential regulation of the human MRP2 and MRP3 gene expression by glucocorticoids.
Multidrug resistance proteins, which catalyse the detoxification of xenobiotics and excretion of metabolites, are very often controlled at the transcriptional level by interaction of exogenous compounds or hormones with nuclear receptors. Since synthetic glucocorticoids have found extensive use as anti-inflammatory drugs, also in the inhaled form in the treatment of asthma, lung cancer is potentially highly prone to transcriptional induction of multidrug resistance proteins by these steroids. MRP3 and MRP2 are major active anionic conjugate transporters in human cells and play a significant role in clinical multidrug resistance in cancer. A549 cells (non-small-cell lung cancer cell line) were challenged with glucocorticoids (dexamethasone, hydrocortisone and prednisone) at physiologically and therapeutically relevant concentrations for 24h and changes in MRP2 and MRP3 expression were followed on four levels: promoter regulation (luciferase reporter constructs), mRNA level (semi-quantitative real-time PCR), protein level (Western blotting) and activity (drug resistance and cellular transport of the model substrate calcein). DEX and HCT in the submicromolar concentration range caused a 2-fold induction of transcriptional activity at the MRP3 promoter construct, while MRP2 expression was not activated. All investigated glucocorticoids caused a modest stimulation of organic anion transport activity. We conclude that glucocorticoids used in clinical practice have the ability to transcriptionally upregulate human MRP3 gene expression in lung-derived cells where this protein is a major component of the organic anion extrusion system. This phenomenon has to be taken into account when designing treatments for lung cancer, especially for patients treated simultaneously with glucocorticoids against inflammatory symptoms.
Pułaski
Lukasz
L
Laboratory of Transcriptional Regulation, Centre of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Łódź, Poland. lpulaski@bio.uni.lodz.pl
Kania
Katarzyna
K
Ratajewski
Marcin
M
Uchiumi
Takeshi
T
Kuwano
Michihiko
M
Bartosz
Grzegorz
G
D003907:Dexamethasone / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D008168:Lung / Q000166:cytology; D026901:Membrane Transport Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D011241:Prednisone / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D003907:Dexamethasone; D005938:Glucocorticoids; D006854:Hydrocortisone; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011241:Prednisone; D012333:RNA, Messenger; C000715087:ABCC2 protein, human; C114462:multidrug resistance-associated protein 3