Research Paper Volume 11, Issue 23 pp 11329—11346

Interplay of MKP-1 and Nrf2 drives tumor growth and drug resistance in non-small cell lung cancer

Hongyan Wang 1, *, , Kaihua Liu 1, *, , Zhexu Chi 2, , Xihang Zhou 2, , Guoping Ren 3, , Ren Zhou 4, 5, , Yinyan Li 1, , Xiuwen Tang 2, , Xiu Jun Wang 1, ,

  • 1 Department of Pharmacology and Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310058, PR China
  • 2 Department of Biochemistry, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310058, PR China
  • 3 Department of Pathology of the First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310003, PR China
  • 4 Institute of Pathology and Forensic Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310058, PR China
  • 5 Department of Pathology and Path-physiology, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310058, PR China
* Equal contribution

received: September 4, 2019 ; accepted: November 18, 2019 ; published: December 6, 2019 ;

https://doi.org/10.18632/aging.102531
How to Cite

Copyright © 2019 Wang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Alterations in KEAP1/ NF-E2 p45-related factor 2 (NFE2L2/Nrf2) signaling pathway have been reported in 23% lung adenocarcinoma patients, suggesting that deregulation of the pathway is a major cancer driver. Here we report that mitogen-activated protein (MAP) kinase phosphatase 1 (MKP-1) drives tumor growth and drug resistance by up regulating transcription factor Nrf2. In non-small cell lung cancer (NSCLC) cells and xenografts, MKP-1 knockdown triggered the down-regulation of the metabolic enzymes and cytoprotective proteins, which are the target genes of Nrf2. Consequently, the cell growth was markedly inhibited with decrease of tumor metabolisms and GSH contents. Moreover, MKP-1 silencing sensitized NSCLC cells to cisplatin treatment. Mechanistically, MKP-1 inhibited the ubiquitylation of Nrf2 via a direct interaction with the transcription factor. Nrf2 was hence stabilized and its transcriptional program was activated. Notably, Nrf2 elevated MKP-1 expression at transcriptional level. In human lung adenoma tumor samples, high levels of expression of MKP-1, Nrf2, and its target gene heme oxygenase 1 were closely correlated. Thus, MKP-1 and Nrf2 form a forward feedback loop in lung cancer cells, which stabilizing and activating Nrf2 to promote anabolic metabolism and GSH biosynthesis. This study uncovers a novel role of MKP-1 in the malignant evolution of cancers.

Abbreviations

AKR1C: aldo-keto reductases 1C1 and 1C2; ARE: antioxidant response element; DMSO: dimethyl sulfoxide; ERK: extracellular signal-regulated kinase; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GCLC: glutamate-cysteine ligase: catalytic subunit; G6PD: glucose-6-phosphate dehydrogenase; GSH: reduced glutathione; GSK-3: glycogen synthase kinase-3; HO-1: heme oxygenase 1; IDH1: isocitrate dehydrogenase 1; JNK: c-Jun NH2-terminal kinase; KEAP1: Kelch-like ECH-associated protein 1; LUAD: lung adenocarcinoma; MAPK: mitogen-activated protein kinase; ME1: malic enzyme 1; MEF: mouse embryonic fibroblast; MKP-1: mitogen-activated protein kinase phosphatase 1; MTHFD2: methylenetetrahydrofolate dehydrogenase 2; Neh: Nrf2-ECH homology; NQO1: NAD(P)H:quinone oxidoreductase 1; Nrf2: NF-E2 p45-related factor 2; NSCLC: non-small cell lung cancer; PGD: phosphogluconate dehydrogenase; PPAT: phosphoribosyl pyrophosphate amidotransferase; PPP: pentose phosphate pathway; RT-PCR: real-time quantitative PCR; siRNA: small interfering RNA; TKT: transketolase; TALDO1: transaldolase 1.