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

Autor: Huang Hui Chen, Hsin Huei Chang, Shu Ying Cheng, Chih Hsiang Huang, Chiung-Tong Chen, Man Wu Sun, Ya Chu Tang, Yung-Chi Cheng, Ching Chuan Kuo, Li Mei Lin, Jang Yang Chang
Rok vydání: 2017
Předmět:
Proto-Oncogene Proteins B-raf
0301 basic medicine
Transcription
Genetic
Cell Survival
NF-E2-Related Factor 2
Antineoplastic Agents
Apoptosis
digestive system
environment and public health
Biochemistry
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
RNA interference
Physiology (medical)
Humans
Gene silencing
RNA
Small Interfering
Promoter Regions
Genetic
Gene
Etoposide
Histone Acetyltransferases
biology
Chemistry
Activator (genetics)
Acetylation
Promoter
Glutathione
respiratory system
Gene Expression Regulation
Neoplastic
DNA Topoisomerases
Type II
030104 developmental biology
Doxorubicin
Drug Resistance
Neoplasm
030220 oncology & carcinogenesis
Cancer cell
ABCC1
biology.protein
Cancer research
Multidrug Resistance-Associated Proteins
HeLa Cells
Signal Transduction
Zdroj: Free Radical Biology and Medicine. 113:505-518
ISSN: 0891-5849
DOI: 10.1016/j.freeradbiomed.2017.10.375
Popis: 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.
Databáze: OpenAIRE
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