A new aspect on glutathione-associated biological function of MRP/GS-X pump and its gene expression.

The biological function as well as gene expression of the MRP/GS-X pump is closely linked with cellular GSH metabolism. This article describes two important aspects, i.e., 1) a role of the MRP/GS-X pump in the modulation of cell cycle arrest induced by anticancer prostaglandins; 2) coordinated up-regulation of gamma-glutamylcysteine synthetase gamma-GCS) and MRP1 genes. The A and J series of prostaglandins (PGs) accumulate in the nuclei to suppress the proliferation of cancer cells. Delta(7)-Prostaglandin A(1) (Delta(7)-PGA(1)) methyl ester, a synthetic anticancer PG, increased the mRNA level of the cyclin-dependent kinase inhibitor p21(Sdi1/CIP1/WAF1) in human leukemia HL-60 cells. The induction of p21(Sdi1/CIP1/WAF1) was associated with the accumulation of hypophosphorylated retinoblastoma protein (pRB) and the suppression of c-myc gene expression. Unlike HL-60 cells, cisplatin-resistant HL-60/R-CP cells were insensitive to Delta(7)-PGA(1) methyl ester. While c-myc expression was transiently suppressed, neither G1 arrest nor hypophosphorylation of pRB was observed with the anticancer PG. Plasma membrane vesicles from HL-60/R-CP cells showed an enhanced level of GS-X pump activity toward the glutathione S-conjugate of Delta(7)-PGA(1) methyl ester. GIF-0019, a potent inhibitor of the GS-X pump, dose-dependently enhanced the cellular sensitivity of HL-60/R-CP cells to Delta(7)-PGA(1) methyl ester, resulting in G1 arrest. The GS-X pump is suggested to play a pivotal role in modulating the biological action of the anticancer PG. The expression of MRP1 and gamma-GCS genes can be coordinately up-regulated by cisplatin, 1-[5-(4-amino-2-methyl)pyrimidyl]methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU), and heavy metals in human cancer cells. For the up-regulation of these genes, both transcriptional and posttranscriptional regulations are considered to be involved.