NRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis

Hui Wang, Xiufei Liu, Min Long, Yi Huang, Linlin Zhang, Rui Zhang, Yi Zheng, Xiaoyu Liao, Yuren Wang, Qian Liao, Wenjie Li, Zili Tang, Qiang Tong, Xiaocui Wang, Fang Fang, Montserrat Rojo De La Vega, Qin Ouyang, Donna D. Zhang, Shicang Yu, Hongting Zheng

Research output: Contribution to journalReview articlepeer-review

168 Scopus citations


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 a-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 upregulated expression of metastasis-associated proteins, increased cancer cell migration, and promotion of metastasis in xenograft mouse models. Accordingly, knockdown of NRF2 attenuated 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.

Original languageEnglish (US)
Article number334ra51
JournalScience translational medicine
Issue number334
StatePublished - Apr 13 2016

ASJC Scopus subject areas

  • Medicine(all)


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