NRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis
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Updated: Mar 22, 2026
Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo
Published on: July 20, 2019
Hui Wang1, Xiufei Liu1, Min Long1
1Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
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 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.
Insights
Common diabetes drugs like DPP-4 inhibitors and alpha-lipoic acid do not cause cancer but may increase metastasis risk by activating NRF2 signaling. Caution is advised for cancer patients on these medications.
Area of Science:
- Oncology
- Endocrinology
- Pharmacology
Background:
- Cancer is a frequent comorbidity in diabetic patients.
- The impact of antidiabetic medications on tumor progression is not well understood.
Purpose of the Study:
- To investigate the effects of common type 2 diabetes mellitus drugs on tumor metastasis.
- To elucidate the molecular mechanisms underlying drug-induced metastasis, focusing on NRF2 signaling.
Main Methods:
- Utilized saxagliptin and sitagliptin (DPP-4 inhibitors) and alpha-lipoic acid (ALA) in preclinical models.
- Examined the role of Nuclear Factor E2-related Factor 2 (NRF2) pathway activation and its downstream effects on metastasis.
- Analyzed human liver cancer tissue samples for NRF2 expression correlation with metastasis.
Main Results:
- DPP-4 inhibitors and ALA did not increase tumor incidence but enhanced metastasis risk in existing tumors.
- These drugs prolonged NRF2 activation by inhibiting KEAP1-dependent NRF2 degradation, upregulating metastasis-associated proteins.
- NRF2 knockdown reduced metastasis, while NRF2 activation accelerated it; increased NRF2 expression correlated with metastasis in human liver cancer.
Conclusions:
- Antioxidants activating NRF2 signaling may increase metastasis risk in cancer patients, including those with diabetes.
- NRF2 signaling represents a potential therapeutic target and biomarker for managing tumor metastasis.
- Antidiabetic drugs like DPP-4 inhibitors warrant cautious use in diabetic cancer patients due to potential metastasis risks.
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