NRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis.
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Author
Wang, HuiLiu, Xiufei
Long, Min
Huang, Yi
Zhang, Linlin
Zhang, Rui
Zheng, Yi
Liao, Xiaoyu
Wang, Yuren
Liao, Qian
Li, Wenjie
Tang, Zili
Tong, Qiang
Wang, Xiaocui
Fang, Fang
Rojo de la Vega, Montserrat
Ouyang, Qin
Zhang, Donna D
Yu, Shicang
Zheng, Hongting
Affiliation
Univ Arizona, Coll Pharm, Dept Pharmacol & ToxicolIssue Date
2016-04-13
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AMER ASSOC ADVANCEMENT SCIENCECitation
NRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis. 2016, 8 (334):334ra51 Sci Transl MedJournal
Science translational medicineRights
Copyright © 2016, American Association for the Advancement of Science.Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.Abstract
Cancer is a common comorbidity of diabetic patients; however, little is known about the effects that antidiabetic drugs have on tumors. We discovered that common classes of drugs used in type 2 diabetes mellitus, the hypoglycemic dipeptidyl peptidase-4 inhibitors (DPP-4i) saxagliptin and sitagliptin, as well as the antineuropathic α-lipoic acid (ALA), do not increase tumor incidence but increase the risk of metastasis of existing tumors. Specifically, these drugs induce prolonged activation of the nuclear factor E2-related factor 2 (NRF2)-mediated antioxidant response through inhibition of KEAP1-C151-dependent ubiquitination and subsequent degradation of NRF2, resulting in up-regulated expression of metastasis-associated proteins, increased cancer cell migration, and promotion of metastasis in xenograft mouse models. Accordingly, knockdown ofNRF2attenuated naturally occurring and DPP-4i-induced tumor metastasis, whereas NRF2 activation accelerated metastasis. Furthermore, in human liver cancer tissue samples, increased NRF2 expression correlated with metastasis. Our findings suggest that antioxidants that activate NRF2 signaling may need to be administered with caution in cancer patients, such as diabetic patients with cancer. Moreover, NRF2 may be a potential biomarker and therapeutic target for tumor metastasis.Note
Published 13 April 2016. 6 month embargo.ISSN
1946-6242PubMed ID
27075625Version
Final accepted manuscriptAdditional Links
http://stm.sciencemag.org/content/8/334/334ra51ae974a485f413a2113503eed53cd6c53
10.1126/scitranslmed.aad6095
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