Premium
Multidrug resistance P‐glycoprotein/ABCB1/MDR1 protects against apoptosis by reducing cellular ceramides (Cer) induced by cadmium (Cd)
Author(s) -
Lee WingKee,
Torchalski Blazej,
Chakraborty Prabir K,
Thévenod Frank
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.1056.3
Subject(s) - p glycoprotein , apoptosis , microbiology and biotechnology , efflux , chemistry , cytotoxicity , multiple drug resistance , biology , pharmacology , biochemistry , in vitro , antibiotics
Cd damages the kidney by apoptosis, but chronic Cd exposure also leads to cancer. Previously, we showed Cd apoptosis mediated by ceramide‐calpain signaling (Lee, W.‐K., Am J Physiol Cell Physiol 2007), but also Cd‐induced upregulation of the multidrug resistance transporter P‐glycoprotein (MDR1) to promote kidney proximal tubule cell (PTC) survival (Thévenod, F., J Biol Chem 2000). The aim of the study was to investigate mechanisms of MDR1 dependent survival of Cd exposed cells. In MDR1 overexpressing kidney cells (MDR1‐MDCK), toxicity of 10–20 μM Cd and 10–50 μM C 6 Cer (by MTT assay and nuclear staining) was significantly reduced by up to 75% and 60%, respectively, which was abolished by the MDR1 blocker PSC833. Electrical measurements (ECIS) of MDCK and MDR1‐MDCK monolayers ± Cd showed similar effects. Efflux of 109 Cd was not enhanced in MDR1‐MDCK and unaffected by MDR1 inhibitors (PSC833, C219). A diacylglycerol kinase assay revealed lower basal total Cer levels in MDR1‐MDCK (0.31 ± 0.04 μM) than controls (0.49 ± 0.07 μM). Cer levels were increased by 67.2 ± 16.0% in MDCK but only a 21.9 ± 4.8% increase in MDR1‐MDCK by 3 h Cd. Furthermore, induction of MDR1 expression by Wnt signalling (transfection of β‐catenin and TCF4) reduced cell death by Cd in PTC. Rather than exporting Cd, MDR1 seems to confer its protective effects by reducing cellular Cer levels or by efflux of Cer metabolites. Funded by DFG TH 345/10‐1 and TH 345/11‐1