QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schenk, P. W. Articles by Nooter, K. Search for Related Content PubMed PubMed Citation Articles by Schenk, P. W. Articles by Nooter, K.

Anticancer Drug Resistance Induced by Disruption of the Saccharomyces cerevisiae NPR2 Gene: a Novel Component Involved in Cisplatin- and Doxorubicin-Provoked Cell Kill

Section of Experimental Chemotherapy, Department of Medical Oncology, Erasmus University Medical Center Rotterdam, Josephine Nefkens Institute, Rotterdam, the Netherlands (P.W.S., M.B., A.W.M.B., H.B., G.S., K.N.); and Medical Genetics Centre South-West Netherlands, Department of Molecular Genetics, Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, Leiden, the Netherlands (J.A.B., H.D.D., J.B.)

The therapeutic potential of antitumor drugs is seriously limited by the manifestation of cellular drug resistance. We used the budding yeast Saccharomyces cerevisiae as a model system to identify novel mechanisms of resistance to one of the most active anticancer agents, cisplatin. We pinpointed NPR2 (nitrogen permease regulator 2) as a gene whose disruption conferred resistance to cisplatin. In addition, we observed a 4-fold cross-resistance of yeast npr2 cells (i.e., cells from which the NPR2 gene had been disrupted) to the anticancer drug doxorubicin, in combination with hypersensitivity to cadmium chloride. Furthermore, npr2 cells displayed unaltered cellular cisplatin and doxorubicin accumulation and showed an enhanced rate of spontaneous mutation compared with the isogenic parent. These data indicate that the npr2 phenotype overlaps that of the sky1 cells that we characterized previously (Mol Pharmacol 61:659–666, 2002). Therefore, we generated yeast npr2 sky1 double-knockout cells and performed clonogenic survival assays for cisplatin and doxorubicin, which revealed that NPR2 and SKY1 (SR-protein-specific kinase from budding yeast) are epistatic. The double-knockout strain was just as resistant to cisplatin and doxorubicin as the single-knockout strain that was most resistant to either drug. In conclusion, we identified NPR2 as a novel component involved in cell kill provoked by cisplatin and doxorubicin, and our data support the hypothesis that NPR2 and SKY1 may use mutual regulatory routes to mediate the cytotoxicity of these anticancer drugs.

Address correspondence to: Dr. K. Nooter, Department of Medical Oncology, Erasmus University Medical Center Rotterdam, Josephine Nefkens Building room Be422, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. E-mail: k.nooter{at}erasmusmc.nl

This article has been cited by other articles:

				C. Liao, B. Hu, M. J. Arno, and B. Panaretou Genomic Screening in Vivo Reveals the Role Played by Vacuolar H+ ATPase and Cytosolic Acidification in Sensitivity to DNA-Damaging Agents Such as Cisplatin Mol. Pharmacol., February 1, 2007; 71(2): 416 - 425. [Abstract] [Full Text] [PDF]

				K. Ueda, H. Kawashima, S. Ohtani, W.-G. Deng, M. Ravoori, J. Bankson, B. Gao, L. Girard, J. D. Minna, J. A. Roth, et al. The 3p21.3 Tumor Suppressor NPRL2 Plays an Important Role in Cisplatin-Induced Resistance in Human Non-Small-Cell Lung Cancer Cells Cancer Res., October 1, 2006; 66(19): 9682 - 9690. [Abstract] [Full Text] [PDF]

				R.-Y. Huang, M. Eddy, M. Vujcic, and D. Kowalski Genome-Wide Screen Identifies Genes Whose Inactivation Confer Resistance to Cisplatin in Saccharomyces cerevisiae Cancer Res., July 1, 2005; 65(13): 5890 - 5897. [Abstract] [Full Text] [PDF]

				J. Li, F. Wang, K. Haraldson, A. Protopopov, F.-M. Duh, L. Geil, I. Kuzmin, J. D. Minna, E. Stanbridge, E. Braga, et al. Functional Characterization of the Candidate Tumor Suppressor Gene NPRL2/G21 Located in 3p21.3C Cancer Res., September 15, 2004; 64(18): 6438 - 6443. [Abstract] [Full Text] [PDF]