NRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis.

Persistent Link:
http://hdl.handle.net/10150/615617
Title:
NRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis.
Author:
Wang, Hui; Liu, 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 & Toxicol
Issue Date:
2016-04-13
Publisher:
AMER ASSOC ADVANCEMENT SCIENCE
Citation:
NRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis. 2016, 8 (334):334ra51 Sci Transl Med
Journal:
Science translational medicine
Rights:
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:
1946-6242
PubMed ID:
27075625
DOI:
10.1126/scitranslmed.aad6095
Version:
Final accepted manuscript
Additional Links:
http://stm.sciencemag.org/content/8/334/334ra51

Full metadata record

DC FieldValue Language
dc.contributor.authorWang, Huien
dc.contributor.authorLiu, Xiufeien
dc.contributor.authorLong, Minen
dc.contributor.authorHuang, Yien
dc.contributor.authorZhang, Linlinen
dc.contributor.authorZhang, Ruien
dc.contributor.authorZheng, Yien
dc.contributor.authorLiao, Xiaoyuen
dc.contributor.authorWang, Yurenen
dc.contributor.authorLiao, Qianen
dc.contributor.authorLi, Wenjieen
dc.contributor.authorTang, Zilien
dc.contributor.authorTong, Qiangen
dc.contributor.authorWang, Xiaocuien
dc.contributor.authorFang, Fangen
dc.contributor.authorRojo de la Vega, Montserraten
dc.contributor.authorOuyang, Qinen
dc.contributor.authorZhang, Donna Den
dc.contributor.authorYu, Shicangen
dc.contributor.authorZheng, Hongtingen
dc.date.accessioned2016-07-06T01:18:05Z-
dc.date.available2016-07-06T01:18:05Z-
dc.date.issued2016-04-13-
dc.identifier.citationNRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis. 2016, 8 (334):334ra51 Sci Transl Meden
dc.identifier.issn1946-6242-
dc.identifier.pmid27075625-
dc.identifier.doi10.1126/scitranslmed.aad6095-
dc.identifier.urihttp://hdl.handle.net/10150/615617-
dc.description.abstractCancer 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.en
dc.language.isoenen
dc.publisherAMER ASSOC ADVANCEMENT SCIENCEen
dc.relation.urlhttp://stm.sciencemag.org/content/8/334/334ra51en
dc.rightsCopyright © 2016, American Association for the Advancement of Scienceen
dc.titleNRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis.en
dc.typeArticleen
dc.contributor.departmentUniv Arizona, Coll Pharm, Dept Pharmacol & Toxicolen
dc.identifier.journalScience translational medicineen
dc.description.notePublished 13 April 2016. 6 month embargo.en
dc.description.collectioninformationThis 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.en
dc.eprint.versionFinal accepted manuscripten
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