Overexpression of NAD(P)H:quinone oxidoreductase 1 (NQO1) and genomic gain of the NQO1 locus modulates breast cancer cell sensitivity to quinones.

Abstract

AIMS:

Alterations in the expression of antioxidant enzymes are associated with changes in cancer cell sensitivity to chemotherapeutic drugs (menadione and β-lapachone). Mechanisms of acquisition of resistance to pro-oxidant drugs were investigated using a model of oxidative stress-resistant MCF-7 breast cancer cells (Resox cells).

MAIN METHODS:

FISH experiments were performed in tumor biopsy and breast cancer cells to characterize the pattern of the NQO1 gene. SNP-arrays were conducted to detect chromosomal imbalances. Finally, the importance of NQO1 overexpression in the putative acquisition of either drug resistance or an increased sensitivity to quinones by cancer cells was investigated by immunoblotting and cytotoxicity assays.

KEY FINDINGS:

Genomic gain of the chromosomal band 16q22 was detected in Resox cells compared to parental breast cancer MCF-7 cells and normal human mammary epithelial 250MK cells. This genomic gain was associated with amplification of the NQO1 gene in one tumor biopsy as well as in breast cancer cell lines. Using different breast cell models, we found that NQO1 overexpression was a main determinant for a potential chemotherapy resistance or an increased sensitivity to quinone-bearing compounds.

SIGNIFICANCE:

Because NQO1 is frequently modified in tumors at genomic and transcriptomic levels, the impact of NQO1 modulation on breast cancer cell sensitivity places NQO1 as a potential link between cancer redox alterations and resistance to chemotherapy. Thus, the NQO1 gene copy number and NQO1 activity should be considered when quinone-bearing molecules are being utilized as potential drugs against breast tumors.

• Authors: Christophe Glorieux, Juan Marcelo Sandoval, Nicolas Dejeans, Geneviève Ameye, Hélène Antoine Poirel, Julien Verrax, Pedro Buc Calderon
• Journal: Life sciences (Life Sci) Vol. 145 Pg. 57-65 (Jan 15 2016) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 26687450 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Quinones
• NAD(P)H Dehydrogenase (Quinone)
• NQO1 protein, human

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Breast (drug effects, metabolism)
• Breast Neoplasms (drug therapy, genetics)
• Drug Resistance, Neoplasm
• Female
• Gene Dosage
• Genetic Loci
• Humans
• MCF-7 Cells
• NAD(P)H Dehydrogenase (Quinone) (genetics)
• Polymorphism, Single Nucleotide
• Quinones (chemistry, pharmacology)
• Up-Regulation