Research Paper Volume 12, Issue 9 pp 8167—8190

Lycopene prevents carcinogen-induced cutaneous tumor by enhancing activation of the Nrf2 pathway through p62-triggered autophagic Keap1 degradation

Siliang Wang 1, 3, *, , Yuan-Yuan Wu 1, *, , Xu Wang 1, *, , Peiliang Shen 1, , Qi Jia 1, , Suyun Yu 1, , Yuan Wang 1, , Xiaoman Li 1, , Wenxing Chen 1, , Aiyun Wang 1, , Yin Lu 1, 2, ,

  • 1 Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, P.R. China
  • 2 Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing 210023, P.R. China
  • 3 Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, P.R. China
* Equal contribution

received: December 21, 2019 ; accepted: March 30, 2020 ; published: May 4, 2020 ;

https://doi.org/10.18632/aging.103132
How to Cite

Copyright © 2020 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

Biologically active natural products have been used for the chemoprevention of cutaneous tumors. Lycopene is the main active phytochemical in tomatoes. We herein aimed to assess the cancer preventive effects of lycopene and to find potential molecular targets. In chemically-induced cutaneous tumor mice and cell models, lycopene attenuated cutaneous tumor incidence and multiplicity as well as the tumorigenesis of normal cutaneous cells in phase-selectivity (only in the promotion phase) manners. By utilizing a comprehensive approach combining bioinformatics with network pharmacology, we predicted that intracellular autophagy and redox status were associated with lycopene’s preventive effect on cutaneous tumors. Lycopene stimulated the activation of antioxidant enzymes and the translocation of the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) that predominantly maintained intracellular redox equilibrium. The cancer chemopreventive effects were mediated by Nrf2. Further, lycopene enhanced the expression of autophagy protein p62. Therefore this led to the degradation of Keap1(Kelch ECH associating protein 1), the main protein locking Nrf2 in cytoplasm. In conclusion, our study provides preclinical evidence of the chemopreventive effects of lycopene on cutaneous tumors and reveals the mechanistic link between lycopene’s stimulation of Nrf2 signaling pathway and p62-mediated degradation of Keap1 via the autophagy-lysosomal pathway.

Abbreviations

3-MA: 3-Methyladenine; 4-HNE: 4-Hydroxynonenal; 8-OHdG: 8-hydroxy-2'-deoxyguanosine; ANOVA: one way analysis of variance; BC: betweenness centrality; BSA: bovine serum albumin; CAT: catalase; CC: closeness centrality; CHX: cycloheximide; CQ: chloroquine; DC: degree centrality; DMBA: 7, 12-dimethylbenzanthracene; EC: eigenvector centrality; ELISA: enzyme linked immunosorbent assay; FBS: fetal bovine serum; GPx: glutathione peroxidase; GR: glutathione reductase; GSH: glutathione; GSSG: Glutathione disulfide; Keap1: Kelch ECH associating protein 1; LAC: local average connectivity; MAPK: mitogen-activated protein kinase; MEM: minimum essential medium; NC: network centrality; Nrf2: nuclear factor erythroid 2-related factor 2; PA: pretreatment in all phases; PBS: phosphate-buffered saline; PCR: polymerase chain reaction; PI: pretreatment only before initiation; PP: pretreatment only before promotion; PPI: protein-protein interaction; PVDF: polyvinylidene difluoride; ROS: reactive oxygen species; SCC: squamous cell carcinoma; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; SOD: superoxide dismutase; TPA: 12-O-tetradecanoylphorbol-13-acetate; UV: ultraviolet.