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Open AccessArticle

Decoupling of Nrf2 Expression Promotes Mesenchymal State Maintenance in Non-Small Cell Lung Cancer

1
Departments of Pathology, Stony Brook University School of Medicine, Stony Brook, NY 11794, USA
2
Bioinformatics and Stony Brook Cancer Center, Stony Brook University School of Medicine, Stony Brook, NY 11794, USA
*
Author to whom correspondence should be addressed.
Present Address: University of Massachusetts Medical School, Worcester, MA 01655, USA.
Present Address: Department of Genetics, Yale University School of Medicine, New Haven, CT, 06510, USA.
§
Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
University of Wisconsin, Madison, WI 53705, USA.
Cancers 2019, 11(10), 1488; https://doi.org/10.3390/cancers11101488
Received: 31 August 2019 / Revised: 25 September 2019 / Accepted: 29 September 2019 / Published: 2 October 2019
(This article belongs to the Special Issue Metabolic Reprogramming and Vulnerabilities in Cancer)
Epithelial mesenchymal transition is a common mechanism leading to metastatic dissemination and cancer progression. In an effort to better understand this process we found an intersection of Nrf2/NLE2F2 (Nrf2), epithelial mesenchymal transition (EMT), and metabolic alterations using multiple in vitro and in vivo approaches. Nrf2 is a key transcription factor controlling the expression of redox regulators to establish cellular redox homeostasis. Nrf2 has been shown to exert both cancer inhibitory and stimulatory activities. Using multiple isogenic non-small cell lung cancer (NSCLC) cell lines, we observed a reduction of Nrf2 protein and activity in a prometastatic mesenchymal cell state and increased reactive oxygen species. Knockdown of Nrf2 promoted a mesenchymal phenotype and reduced glycolytic, TCA cycle and lipogenic output from both glucose and glutamine in the isogenic cell models; while overexpression of Nrf2 promoted a more epithelial phenotype and metabolic reactivation. In both Nrf2 knockout mice and in NSCLC patient samples, Nrf2low was co-correlated with markedly decreased expression of glycolytic, lipogenic, and mesenchymal RNAs. Conversely, Nrf2high was associated with partial mesenchymal epithelial transition and increased expression of metabolic RNAs. The impact of Nrf2 on epithelial and mesenchymal cancer cell states and metabolic output provide an additional context to Nrf2 function in cancer initiation and progression, with implications for therapeutic inhibition of Nrf2 in cancer treatment. View Full-Text
Keywords: Nrf2; epithelial mesenchymal transition; glycolysis; TCA cycle; lipogenesis; redox signaling Nrf2; epithelial mesenchymal transition; glycolysis; TCA cycle; lipogenesis; redox signaling
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Haley, J.A.; Ruiz, C.F.; Montal, E.D.; Wang, D.; Haley, J.D.; Girnun, G.D. Decoupling of Nrf2 Expression Promotes Mesenchymal State Maintenance in Non-Small Cell Lung Cancer. Cancers 2019, 11, 1488.

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