Frequent coexpression of MRP/GS-X pump and γ-glutamylcysteine synthetase mRNA in drug-resistant cells, untreated tumor cells, and normal mouse tissues

M. Tien Kuo, Jia Ju Bao, Masato Furuichi, Yoshiaki Yamane, Akira Gomi, Niramol Savaraj, Toshio Masuzawa, Toshihisa Ishikawa

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Abstract

Expression of the multidrug resistance protein gene MRP, which confers non-P-glycoprotein-mediated multidrug resistance, has been found in many drug-resistant variants and tumor samples. Recent studies have demonstrated that MRP functions as an ATP-dependent transporter functionally related to the previously described glutathione-conjugate (GS-X) pump. We have shown recently that the MRP and γ-glutamylcysteine synthetase (γ-GCS) heavy subunit mRNA levels are coordinately overexpressed in cisplatin (CP) resistant human leukemia cells (Ishikawa et al., J Biol Chem 271: 14981-14988, 1996) and frequently co-elevated in human colorectal tumors (Kuo et al., Cancer Res 56: 3642-3644, 1996). In the present study, we showed the coexpression patterns of thirteen additional human drug-resistant cell lines representing different tumor cell origins selected with different agents, except for one doxorubicin-selected line which demonstrated minor elevation in MRP mRNA with no detectable increase in γ-GCS mRNA, suggesting that the increase of MRP mRNA preceded the increase in γ-GCS mRNA. Furthermore, in seventeen randomly selected untreated tumor cell lines, the overall correlation coefficient between MRP and γ-GCS mRNA levels was 0.861. In normal mice, the correlation coefficient of mrp and γ-gcs mRNA was 0.662 in fourteen tissues (kidney and liver were not included) analyzed. Kidney and liver expressed low levels of mrp relative to γ-gcs; however, these two tissues expressed high levels of a functionally related mrp homologue, mrp2 (cMoat or cMrp), which may have compensated for the underexpressed mrp in maintaining the total GS-X pump activities. Altogether, these results demonstrated the frequent coexpression of these two genes in various cell settings.

Original languageEnglish
Pages (from-to)605-615
Number of pages11
JournalBiochemical Pharmacology
Volume55
Issue number5
DOIs
StatePublished - Mar 1 1998

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Glutamate-Cysteine Ligase
Tumors
Cells
Tissue
Messenger RNA
Pharmaceutical Preparations
Neoplasms
Liver
Colorectal Neoplasms
Genes
P-Glycoproteins
MDR Genes
Kidney
Multiple Drug Resistance
glutathione transporter
Tumor Cell Line
Doxorubicin
Cisplatin
Glutathione
Glycoproteins

Keywords

  • γ-Glutamylcysteine synthetase
  • Antitumor drugs
  • Chemotherapy
  • Gene regulation
  • Multidrug-resistance protein

ASJC Scopus subject areas

  • Pharmacology

Cite this

Frequent coexpression of MRP/GS-X pump and γ-glutamylcysteine synthetase mRNA in drug-resistant cells, untreated tumor cells, and normal mouse tissues. / Kuo, M. Tien; Bao, Jia Ju; Furuichi, Masato; Yamane, Yoshiaki; Gomi, Akira; Savaraj, Niramol; Masuzawa, Toshio; Ishikawa, Toshihisa.

In: Biochemical Pharmacology, Vol. 55, No. 5, 01.03.1998, p. 605-615.

Research output: Contribution to journalArticle

Kuo, M. Tien ; Bao, Jia Ju ; Furuichi, Masato ; Yamane, Yoshiaki ; Gomi, Akira ; Savaraj, Niramol ; Masuzawa, Toshio ; Ishikawa, Toshihisa. / Frequent coexpression of MRP/GS-X pump and γ-glutamylcysteine synthetase mRNA in drug-resistant cells, untreated tumor cells, and normal mouse tissues. In: Biochemical Pharmacology. 1998 ; Vol. 55, No. 5. pp. 605-615.
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AU - Furuichi, Masato

AU - Yamane, Yoshiaki

AU - Gomi, Akira

AU - Savaraj, Niramol

AU - Masuzawa, Toshio

AU - Ishikawa, Toshihisa

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