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.
Highlights
As one of the most common cancers worldwide, cutaneous carcinoma has over one million new cases each year, with annual cost for treatment surpassing 8 billion dollars [1, 2]
We identified the endogenous interaction between Keap1 and p62 as well as the degradation of Keap1 in an autophagy-lysosomal manner after treatment with lycopene, which protected Nrf2 from Keap1-induced proteasomal degradation
A two-stage 7, 12-dimethylbenzanthracene (DMBA)/ 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced model, which has been used in our group and other labs for years as a successful mouse model of cutaneous papilloma, was first employed [17] (Figure 1A)
Summary
As one of the most common cancers worldwide, cutaneous carcinoma has over one million new cases each year, with annual cost for treatment surpassing 8 billion dollars [1, 2]. It still cannot be effectively treated in regards to both poor clinical outcomes and out-of-pocket expenditure [3, 4]. The preventive effects of this compound applied topically and the underlying mechanisms remain unclear To this end, we utilized two models of chemically induced tumorigenesis to evaluate the chemopreventive effects of lycopene in vivo and in vitro
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