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Free Radic Biol Med. 2017 Dec;113:505-518. doi: 10.1016/j.freeradbiomed.2017.10.375. Epub 2017 Nov 5.

Enhanced B-Raf-mediated NRF2 gene transcription and HATs-mediated NRF2 protein acetylation contributes to ABCC1-mediated chemoresistance and glutathione-mediated survival in acquired topoisomerase II poison-resistant cancer cells.

Author information

1
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan 35053, Taiwan.
2
National Institute of Cancer Research, National Health Research Institutes, Zhunan 35053, Taiwan; Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 70101, Taiwan; Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
3
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan 35053, Taiwan; Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 30013, Taiwan.
4
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510, USA.
5
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan 35053, Taiwan; Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan; Graduate Program for Aging, China Medical University, Taichung 40402, Taiwan. Electronic address: cckuo@nhri.org.tw.

Abstract

Nuclear factor erythroid-2-related factor 2 (NRF2) mainly regulates transcriptional activation through antioxidant-responsive elements (AREs) present in the promoters of NRF2 target genes. Recently, we found that NRF2 was overexpressed in a KB-derived drug-resistant cancer cell panel. In this panel, KB-7D cells, which show acquired resistance to topoisomerase II (Top II) poisons, exhibited the highest NRF2 activation. To investigate whether NRF2 directly contributed to acquired resistance against Top II poisons, we manipulated NRF2 by genetic and pharmacological approaches. The result demonstrated that silencing of NRF2 by RNA interference increased the sensitivity and treatment with NRF2 activator decreased the sensitivity of KB and KB-7D cells toward Top II poisons. Further, increased B-Raf-mediated NRF2 gene transcription and HATs-mediated NRF2 protein acetylation activated NRF2 signaling in KB-7D cells. Moreover, increased binding of NRF2 to an ARE in the promoter of ATP-binding cassette subfamily C member 1 (ABCC1) directly contributed to Top II poison resistance. In addition, activation of NRF2 increased glutathione level and antioxidant capacity in KB-7D cells compared with that in KB cells; moreover, high glutathione level provided survival advantage to KB-7D cells. Our study is the first to show that aberrant NRF2 activation is via increased B-Raf-mediated NRF2 gene transcription and HATs-mediated NRF2 protein acetylation, which increases the acquired resistance and promote the survival of Top II poison-resistant cancer cells. Importantly, NRF2 downstream effectors ABCC1 and glutathione directly contribute to acquired resistance and survival, respectively. These results suggest that blockade of NRF2 signaling may enhance therapeutic efficacy and reduce the survival of Top II poison-refractory tumors in clinical.

KEYWORDS:

ABCC1; Acquired resistance; Glutathione; NRF2; Topoisomerase II poisons

[Indexed for MEDLINE]

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