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

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• 作者：Christophe Glorieux^a ; Juan Marcelo Sandoval^a ; Nicolas Dejeans^a ; ¹ ; Geneviè ; ve Ameye^b ; Hé ; lè ; ne Antoine Poirel^b ; Julien Verrax^a ; Pedro Buc Calderon^a ; ^c ; ^{pedro.buccalderon@uclouvain.be" class="auth_mail" title="E-mail the corresponding author}
• 关键词：NQO1 ; Breast cancer cells ; Genomic gain ; Menadione ; β-Lapachone ; Redox alterations
• 刊名：Life Sciences
• 出版年：2016
• 出版时间：15 January 2016
• 年：2016
• 卷：145
• 期：Complete
• 页码：57-65
• 全文大小：855 K

文摘

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.