## 3 Keep1-Nrf2-ARE Signaling System
### Lycopene (LP)  
Lycopene (**11**) is an aliphatic hydrocarbon carotenoid compound. It is found in several dietary plants including papayas, tomatoes, and watermelons [50]. LP, a master regulator of oxidative stress, has previously been shown to exhibit anti-proliferative, antioxidant and anti-inflammatory properties [50; 242]. Several studies using in vitro and in vivo experimental models have shown that the concentration of LP in serum and tissue can prevent the formation of human prostate cancer [243]. The amelioration of prostate cancer by LP might be both Nrf2 dependent and independent [244]. The role of Nrf2 and its antioxidant enzymes might vary in androgen-dependent and -independent prostate cancer cells. For instance, LP mediated a greater enhancement of GSH, GCL, GST-\(\pi\), NQO1 and Nrf2 expressions in androgen-resistant DU145 cells than in androgen-dependent C4-2 cells [245]. Mechanistically, one study suggested the downregulation of AKT2 expression by LP in treating prostate cancer [246]. The suppression of NF-kB expression was also implicated in the management of prostate and breast cancer [247]. A recent study reported that LP enhanced the cisplatin sensitivity to cervical cancer cells by abolishing cell viability, enhancing Bax and suppressing Bcl-2 expressions [248]. Here, LP abrogated the NF-kB-induced inflammatory pathway and enhanced Nrf2 expression, recucing oxidative stress. LP downregulated the expression of MMP-7 by blocking the phosphorylation of ERK1/2, GSK-3\(\beta\), and AKT/PI3K in HT-29 colorectal cancer cells in order to exert its chemotherapeutic role [249]. In MDA-MB-468 breast cancer cells, LP exhibited potential chemotherapeutic properties, whereby it provided promising ERK1/2 activation and inhibition of AKT phosphorylation and its downstream target mTOR [250]. It upregulated the Nrf2 dependent antioxidant enzymes HO-1 and GSH in endothelial cells [251]. In addition, it blocked the expression of TNF-\(\alpha\) and NF-\(\kappa\)B activation in the same cells. Studies on human colorectal and prostate cancers demonstrated that LP actively reduced inflammation in cancer cells by inhibiting the release of inflammatory cytokines like iNOS, COX-2, prostaglandin E2, nitric oxide, IL-1\(\beta\), IL-6, and TNF-\(\alpha\), thereby blocking the activation of NF-\(\kappa\)B and JNK [252; 253]. LP exhibited antioxidant and anti-inflammatory activities in retinal pigment epithelium cells by abolishing ICAM-1 expression and inhibiting NF-\(\kappa\)B activation [254]. In addition, it enhanced Nrf2 expression in nuclear extracts, facilitating the transactivity of the AREs and therefore increasing the intracellular GSH and GCL expression. LP prevented ovarian cancer in laying hens by reducing the serum level of MDA and abrogating the expression of NF-kB [255]. Additionally, Nrf2 and HO-1 expressions were enhanced, whereas STAT3 expression was suppressed by LP. Hepatocarcinogenesis was prevented by LP as a consequence of diminished oxidative stress [256; 257]. Here, Nrf2, HO-1, CAT, SOD and Gpx expressions were enhanced, inflammatory cytokines TNF-\(\alpha\), IL-1\(\beta\) and IL-12 were reduced, and NF-kB, COX-2, ERK, and AKT/mTOR activations were suppressed. LP ameliorated cutaneous tumors by stimulating the Nrf2 signaling pathway and causing p62-regulated degradation of Keap1 through a unique lysosome-mediated autophagic mechanism [258]. LP also improved DMBA/12-O-tetradecanoylphorbol-13-acetate (TPA)-mediated oxidative stress and skin carcinogenesis in a mouse model [259]. Here, it promoted nuclear translocation of Nrf2, enhanced the levels of CAT, HO-1, Gpx, SOD and GR, and thereby prevented ROS and MDA generation. A recent review on the mechanism of chemotherapeutic potential of LP reported that modulation of Nrf2/NF-\(\kappa\)Btranscription played the key role in treating different malignancies [260]. It is known that chronic inflammation is a big driving factor in the process of tumor relapse and further carcinogenesis.