Frequent coexpression of MRP/GS-X pump and gamma-glutamylcysteine synthetase mRNA in drug-resistant cells, untreated tumor cells, and normal mouse tissues.
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 gamma-glutamylcysteine synthetase (gamma-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 gamma-GCS mRNA, suggesting that the increase of MRP mRNA preceded the increase in gamma-GCS mRNA. Furthermore, in seventeen randomly selected untreated tumor cell lines, the overall correlation coefficient between MRP and gamma-GCS mRNA levels was 0.861. In normal mice, the correlation coefficient of mrp and gamma-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 gamma-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.
Kuo
M T
MT
Department of Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA. t_kuo@path.mda.tmc.edu
Bao
J
J
Furuichi
M
M
Yamane
Y
Y
Gomi
A
A
Savaraj
N
N
Masuzawa
T
T
Ishikawa
T
T
D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004351:Drug Resistance / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005721:Glutamate-Cysteine Ligase / Q000235:genetics*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010446:Peptide Fragments / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics*; D014407:Tumor Cells, Cultured
D018528:ATP-Binding Cassette Transporters; D005721:Glutamate-Cysteine Ligase; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010446:Peptide Fragments; D012333:RNA, Messenger