Induction ofMRP1 and ?-glutamylcysteine synthetase gene expression by interleukin 1? is mediated by nitric oxide-related signalings in human colorectal cancer cells

Abstract

Treatment of human colorectal cancer cells HT29 with interleukin 1beta (IL-1beta) induces expression of the multidrug resistance protein (MRP1) gene encoding the ATP-dependent glutathione S-conjugate export (GS-X) pump and the gamma-glutamylcysteine synthetase (gamma-GCSh) gene encoding heavy (catalytic) subunit of gamma-glutamylcysteine synthetase, the rate-limiting enzyme for the biosynthesis of glutathione (GSH). The induction can be suppressed by N(G)-methyl-L-arginine, a specific inhibitor of nitric oxide synthase (NOS). These results suggest that IL-1beta-mediated MRP1 and gamma-GCSh induction involve nitric oxide (NO) -related signaling. Further supports to the involvement of NO in the induction of MRP1 and gamma-GCSh expression are made by the following observations. (i) Expression of MRP1 and gamma-GCSh genes were induced by treating the cells with NO donors, i.e., S-nitro-N-acetyl-D,L-penicillamide (SNAP) and S-nitroso-L-glutathione, in a concentration-dependent manner. (ii) Ectopic expression of inducible NOS (iNOS) activity by transfecting expressible recombinant iNOS cDNA encoding functional iNOS but not the nonfunctional version resulted in elevated expression of MRP1 and gamma-GCSh. We also demonstrated that HT-29 cells treated with either 1L-1beta or SNAP induced ceramide production, and addition of C2 or C6 ceramides into cultured HT-29 cells resulted in induction of gamma-GCSh but not MRP1 expression. Collectively, our results demonstrate that induction of MRP1 and gamma-GCSh by IL-1beta is regulated, at least in part, by an NO-related signaling, and induction of gamma-GCSh is by NO-related ceramide signaling.

Delayed Mechanism for Induction of γ-Glutamylcysteine Synthetase Heavy Subunit mRNA Stability by Oxidative Stress Involving p38 Mitogen-activated Protein Kinase Signaling

“…We demonstrated previously that expression of ␥-GCSh could be induced by many cytotoxic agents, including antitumor agents (10,11), heavy metals (11), carcinogens (12), and prooxidants (13)(14)(15)(16). All of these treatments, to various extents, induce intracellular reactive oxygen species imbalance.…”

Inflammatory Cytokines, but Not Bile Acids, Regulate Expression of Murine Hepatic Anion Transporters in Endotoxemia

“…Changes at the post-transcriptional level such as protein stability could also be involved. An induction of Mrp1 mRNA expression was seen also in IL-1␤-treated Hepa 1-6 cells, similar to that which has also been reported in human hepatoma cells (Ikegami et al, 2000;Lee and PiquetteMiller, 2001). Likewise, neither Mrp-mediated efflux of 5-CF nor mRNA levels were significantly altered by treatment with bile acids.…”

Redox Regulation of Multidrug Resistance in Cancer Chemotherapy: Molecular Mechanisms and Therapeutic Opportunities

“…As with ␥-GCSh, our laboratory has demonstrated that expression of MRP1 in cultured cells can be induced by a variety of cytotoxic agents, including prooxidants (155), heavy metals (109), carcinogens (282), antitumor agents, and nitric oxides (106). These observations raise an interesting scenario that mechanisms underlying induced expression of MRP1 and ␥-GCSh may be co-regulated.…”

“…Transcriptional regulation. Our laboratory previously demonstrated that expression of ␥-GCSh can be induced by a number of cytotoxic challenges, including antitumor agents (77,109), heavy metals (109), carcinogens (282), and prooxidants (106,282). All these inducers, at the concentrations used, exert various degrees of oxidative stresses.…”