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Nrf2 induces cisplatin resistance through activation of autophagy in ovarian carcinoma.
MedLine Citation:
PMID:  24817946     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
METHODS: The human ovarian carcinoma cell line, A2780, and its cisplatin-resistant variant, A2780cp were cultivated. Cell viability was determined with WST-8 assay. Western blot was applied to detect the expression of Nrf2, Nrf2 target genes, and autophagy-related proteins. RNA interference was used to knock down target genes. Annexin V and propidium iodide (PI) staining was utilized to quantify apoptosis. The ultrastructural analysis of autophagosomes was performed by transmission electron microscopy (TEM).
RESULTS: Nrf2 and its targeting genes, NQO1 and HO-1, are overexpressed in A2780cp cells compared with A2780 cells. Knocking down Nrf2 sensitized A2780cp cells to cisplatin treatment and decreased autophagy-related genes, Atg3, Atg6, Atg12 and p62 in both mRNA and protein levels. Furthermore, we demonstrated that in both cell lines cisplatin could induce the formation of autophagosomes and upregulate the expression of autophagy-related genes Atg3, Atg6 and Atg12. Treatment with an autophagy inhibitor, 3-Methyladenine (3-MA), or beclin 1 siRNA enhanced cisplatin-induced cell death in A2780cp cells, suggesting that inhibition of autophagy renders resistant cells to be more sensitive to cisplatin. Taken together, Nrf2 signaling may regulate cisplatin resistance by activating autophagy.
CONCLUSIONS: Nrf2-activated autophagy may function as a novel mechanism causing cisplatin-resistance.
Authors:
Ling-Jie Bao; Melba C Jaramillo; Zhen-Bo Zhang; Yun-Xi Zheng; Ming Yao; Donna D Zhang; Xiao-Fang Yi
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Publication Detail:
Type:  Journal Article     Date:  2014-03-15
Journal Detail:
Title:  International journal of clinical and experimental pathology     Volume:  7     ISSN:  1936-2625     ISO Abbreviation:  Int J Clin Exp Pathol     Publication Date:  2014  
Date Detail:
Created Date:  2014-05-12     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101480565     Medline TA:  Int J Clin Exp Pathol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1502-13     Citation Subset:  IM    
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