title: NRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis.
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.
authors.affiliation: Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Xiufei
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Min
authors.initials: M
authors.lastname: Long
authors.affiliation: Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing Key Laboratory of Immunity and Infectious Diseases, Children's Hospital of Chongqing Medical University, Chongqing 400014, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Liao
authors.affiliation: Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Yuren
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Liao
authors.affiliation: Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Li
authors.affiliation: Molecular and Translational Radiation Oncology, Heidelberg Ion Therapy Center, Heidelberg Institute of Radiation Oncology, University of Heidelberg Medical School, National Center for Cancer Diseases, German Cancer Research Center, Heidelberg 69120, Germany.
authors.forename: Zili
authors.initials: Z
authors.lastname: Tang
authors.affiliation: Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Tong
authors.affiliation: Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Xiaocui
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Fang
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Rojo de la Vega
authors.affiliation: College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Ouyang
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA. fnf7703@hotmail.com yushicang@163.com dzhang@pharmacy.arizona.edu.
authors.forename: Donna D
authors.initials: DD
authors.lastname: Zhang
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China. fnf7703@hotmail.com yushicang@163.com dzhang@pharmacy.arizona.edu.
authors.forename: Shicang
authors.initials: S
authors.lastname: Yu
authors.affiliation: Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China. fnf7703@hotmail.com yushicang@163.com dzhang@pharmacy.arizona.edu.
authors.forename: Hongting
authors.initials: H
authors.lastname: Zheng
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000494:pharmacology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009362:Neoplasm Metastasis / Q000473:pathology*; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects; D000068900:Sitagliptin Phosphate / Q000494:pharmacology; D008063:Thioctic Acid / Q000494:pharmacology; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D000975:Antioxidants; D014408:Biomarkers, Tumor; D004151:Dipeptides; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D008063:Thioctic Acid; C502994:saxagliptin; C546365:GCLM protein, human; D005721:Glutamate-Cysteine Ligase; D000218:Adamantane; D000068900:Sitagliptin Phosphate