Overexpression of ZNRD1 Promotes Multidrug-Resistant Phenotype of Gastric Cancer Cells Through Upregulation of P-Glycoprotein

Abstract

ZNRD1, a new zinc ribbon gene, has been previously identified as an upregulated gene in a multidrug-resistant gastric cancer cell line SGC7901/VCR comparing to its parental cell SGC7901 by subtractive hybridization and RT-PCR. The antisense nucleic acid for ZNRD1 could enhance adriamycin accumulation in SGC7901/VCR cells and sensitize SGC7901/VCR cells to vincristine. The present study aims to explore the role of ZNRD1 in multidrug resistance in gastric cancer cells. Upregulation of ZNRD1 protein in SGC7901/VCR cells was confirmed by Western blot and immunocytochmical staining. ZNRD1 was genetically overexpressed in SGC7901 cells by gene transfection. It was found that overexpression of ZNRD1 could sensitize SGC7901 cells to P-glycoprotein (P-gp)-related anticancer drugs (vincristine, adriamycin, etoposide) but not to P-gp-nonrelated drugs (5-fluorouracil and cisplatin), which was accompanied with significantly decreased adriamycin accumulation and retention and increased adriamycin releasing in SGC7901 cells. Verapamil, an inhibitor for P-gp, could reverse the effects of ZNRD1 on drug sensitivity and drug accumulation in SGC7901 cells to a great extent. Western blot and Northern blot revealed that overexpression of ZNRD1 could upregulate P-gp at both protein and mRNA levels. Together, these results suggest that overexpression of ZNRD1 could promote multidrug-resistant phenotype of gastric cancer cells through upregulation of P-gp.

Zinc ribbon domain-containing 1 (ZNRD1) mediates multidrug resistance of leukemia cells through regulation of P-glycoprotein and Bcl-2

“…It was interesting that HL-60/ vincristine, selected by drug resistance to vincristine, showed resistance not only to P-gp-related vincristine and Adriamycin but also to 5-FU, CDDP, and mitomycin C (Table 1). This was consistent with previous report that vincristine-induced resistant gastric cancer cell line SGC7901/vincristine and Adriamycin-induced resistant gastric cancer cell line SGC7901/Adriamycin showed resistance not only to typical MDR drugs but also to non-P-gp-related drugs (11,12,20).…”

Upregulation of ZNRD1 Enhances Cisplatin Resistance in Human Esophageal Cancer Cells by Regulation of ERCC1 and Bcl-2

“…Our results of Western blots demonstrated that the overexpression of ZNRD1 induced enhanced expression of P-gp but unchanged expression of MRP, which was consistent with previous studies [24] . However, since the CDDP is not a substrate for P-gp, we presumed that the enhanced expression of P-gp was not the major mechanism of ZNRD1-induced CDDP resistance in esophageal cells.…”

“…A previous study revealed that ZNRD1 was related to the multidrug resistance of gastric cancer, and the zinc-ribbon domains contained in ZNRD1 might enhance expression of P-gp by binding to the MDR1 promoter in the same way as zinc fingers [24] . However, there was no further understanding of the relation between the expression of ZNRD1 and CDDP resistance.…”

Proteasome inhibitor MG132 reverses multidrug resistance of gastric cancer through enhancing apoptosis and inhibiting P-gp

“…But considering that suppression of drug-induced apoptosis and the upregulation of P-gp are the main mechanisms by which gastric cancer cell line SGC7901 develop multidrug resistance, 13,28,29,37 we focused our attention on the effects of MG132 on apoptosis and the regulation of P-gp and thus MG132-reversed MDR of gastric cancer cells. And between the two mechanisms by which MG132 overcome multidrug resistance of gastric cancer, MG132 related apoptosis seemed to play a more important role.…”