Regulation of MDR-1 (P-glycoprotein) by cyclooxygenase-2. J Biol Chem 2002 Oct 11;277(41):38915-20
Date
07/26/2002Pubmed ID
12138126DOI
10.1074/jbc.M206855200Scopus ID
2-s2.0-0037064039 (requires institutional sign-in at Scopus site) 189 CitationsAbstract
Cyclooxygenase-2 (Cox-2), an inducible form of the enzyme that catalyzes the first step in the synthesis of prostanoids, has been shown to be overexpressed in a wide range of tumors and possesses proangiogenic and antiapoptotic properties. To understand the molecular mechanism of Cox-2 action we used adenovirus-mediated transfer of rat Cox-2 cDNA into renal rat mesangial cells and determined the differential gene expression using cDNA microarrays. One of the several genes that were highly up-regulated by over expressed Cox-2 was MDR1. MDR1 or P-glycoprotein (P-gp), the product of the MDR1 gene, is implicated as the primary cause of multidrug resistance (MDR) in tumors where it acts as an efflux pump for chemotherapeutic agents. It is also expressed in normal tissues of the liver and kidney where it functions to actively transport lipophilic xenobiotics. Reverse transcriptase-PCR analysis confirmed the results of the microarray, showing increased mRNA levels for MDR1 in Cox-2 overexpressing cells. This increase in mRNA translated to an increase in MDR1 protein expression, which was dose-dependent on Cox-2 expression. Furthermore, using rhodamine 123 efflux assay we observed a significant increase in P-gp activity in Cox-2 overexpressing renal mesangial cells. The specific Cox-2 inhibitor NS398 was able to block the Cox-2-mediated increase in MDR1 expression and activity, suggesting that Cox-2 products may be implicated in this response. These results prove the existence of a causal link between Cox-2 and P-gp activity, which would have implications for kidney function and multidrug resistance in tumors where Cox-2 is overexpressed.
Author List
Patel VA, Dunn MJ, Sorokin AAuthor
Andrey Sorokin PhD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdenoviridaeAnimals
Cells, Cultured
Cyclooxygenase 2
Enzyme Inhibitors
Fluorescent Dyes
Gene Transfer Techniques
Genes, Reporter
Glomerular Mesangium
Isoenzymes
Male
Oligonucleotide Array Sequence Analysis
Prostaglandin-Endoperoxide Synthases
Rats
Rats, Sprague-Dawley
Rhodamine 123
Transgenes
