RGD Reference Report - Development of multidrug resistance due to multiple factors including P-glycoprotein overexpression under K-selection after MYC and HRAS oncogene activation. - Rat Genome Database

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Development of multidrug resistance due to multiple factors including P-glycoprotein overexpression under K-selection after MYC and HRAS oncogene activation.

Authors: Nakamura, Y  Sato, H  Motokura, T 
Citation: Nakamura Y, etal., Int J Cancer. 2006 May 15;118(10):2448-54.
RGD ID: 2316359
Pubmed: (View Article at PubMed) PMID:16353156
DOI: Full-text: DOI:10.1002/ijc.21691

Multistep tumorigenesis is a form of microevolution consisting of mutation and selection. To clarify the role of selection modalities in tumor development, we examined two alternative evolutionary conditions, r-selection in sparse culture, which allows cells to proliferate rapidly, and K-selection in confluent culture, in which overcrowding constrains cell proliferation. Using MYC- and EJ-RAS-transformed rat embryo fibroblasts, we found that K-selected cells acquired and stably maintained multidrug resistance (MDR) to DOX, VCR, MTX and Ara-C. Then, we examined the involvement of a number of factors potentially causal of the development of MDR, that is, ploidy, Tp53 mutation, doubling time and the expression levels of genes related to drug resistance. Although ploidy status and Tp53 mutations did not correlate with MDR, we found that Abcb1/Mdr1, encoding P-glycoprotein (Pgp), was significantly upregulated after K-selection. Cyclosporin A, a competitive inhibitor of Pgp, increased the intracellular accumulation of DOX and reduced the resistance to it. Indeed, the population of Pgp-transfected cells significantly expanded under K-, but not under r-selection. In addition to Pgp upregulation, altered expression of other genes such as Cda/cytidine deaminase and Slc29a1/equilibrative nucleoside transporter 1 and prolonged doubling times were associated with MDR. This system reproduces events associated with MDR in vivo and would be useful for analysis of MDR development.



Gene Ontology Annotations    

Biological Process

Objects Annotated

Genes (Rattus norvegicus)
Abcb1a  (ATP binding cassette subfamily B member 1A)
Abcb1b  (ATP-binding cassette, subfamily B (MDR/TAP), member 1B)
Cda  (cytidine deaminase)


Additional Information