Journal of Cancer Prevention 2015; 20(2): 92-96
Published online June 30, 2015
© Korean Society of Cancer Prevention
Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul, Korea
Correspondence to :
Hyeyoung Kim, Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-749, Korea Tel: +82-2-2123-3125, Fax: +82-2-364-5781, E-mail: firstname.lastname@example.org, ORCID: Hyeyoung Kim,
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Gastric cancer ranks as the most common cancer and the second leading cause of cancer-related death in the world. Risk factors of gastric carcinogenesis include oxidative stress, DNA damage,
Keywords: Anticancer effect, Lycopene, Gastric carcinogenesis
Gastric cancer is one of the most common cancers in the world, following lung, breast and colorectal cancer.1?3 Risk factors of gastric cancer include poor diet, smoking, family history, inflammation, and
Oxidative stress-mediated DNA damage and tissue injury are related to cancer development.18,19 When the damaged cells divide, DNA duplication and cell metabolism become aberrant. Therefore, mutation is an important factor in carcinogenesis and oxidative damage could lead to carcinogenesis.20,21 Several studies reported that antioxidants inhibit oxidative damage and decrease abnormal cell division.22,23 Protective effect of antioxidants plays a critical role in prevention of cancer. Since gastrointestinal tract could easily be exposed to external and internal stimuli which produce ROS, the levels of antioxidants are especially important for preventing cellular damage. Antioxidants and antioxidant enzymes including glutathione (GSH), glutathione peroxidase (GPx), glutathione-S-transferase (GST) are involved in scavenging oxygen free radicals.24 GSH protects essential cellular components from ROS-mediated damage and regulates cell proliferation. Lycopene, compared to other carotenoids and antioxidants such as α-tocopherol and β-carotene, is a powerful antioxidant with a singlet oxygen quenching activity.25 Treatment of lycopene significantly reduced the extent of lipid peroxidation and enhanced the activities of GSH-dependent enzymes in gastric cancer rats.26 Lycopene reduced oxidative injury by stimulating levels and activities of GSH, GST, GPx enzymes in gastric cancer animals.27,28 These findings demonstrate that lycopene may have anticancer effect by increasing activities of antioxidant enzymes and reducing oxidative damage in gastric mucosa.
ERK signaling is involved in cell cycle checkpoints and mitosis. Therefore, ERK is considered as a major regulator of cell proliferation, apoptosis, and differentiation.29,30 Lycopene increased G0?G1 phase and decreased S phase in human gastric cancer HGC-27 cells.30 Lycopene inhibited phospholylation of ERK in gastric cancer cells as well as hepatocarcinoma cells.30,31 Yang et al.31 reported that enzymatic metabolite of lycopene, apo-8′-lycopena, suppressed protein expression of Rho small GTPases and inhibited focal adhesion kinase-mediated signaling pathway, such as ERK/p38 and phosphatidylinositol 3-kinase-Akt axis. These findings suggest that lycopene may contribute to anti-proliferative effects in gastric cancer cells by inhibiting activation of ERK and inducing cell cycle arrest.
Bcl-2 is considered as an important anti-apoptotic protein and regulates cell death.32 Bcl-2 inhibits apoptosis by reducing caspase activation such as caspase 3 and 8.33 Caspase 3, apoptosis-related cysteine peptidase, interacts with caspase 8. These proteins are involved in the programmed cell death induced by various stimuli.34 Apoptosis regulator Bax protein, a member of Bcl-2 family proteins, promotes apoptosis. As a pro-apoptotic protein, Bax induces release of cytochrome C and other pro-apoptotic factors from the mitochondria, leading to activation of caspases.35 Lycopene induced apoptosis in gastric cancer cells by decreasing Bcl-2 level and increasing the levels of Bax, caspase 3 and 8.33,36
A tumor suppressor gene p53 regulates the balance of cell proliferation and apoptosis. Several studies reported that p53 is overexpressed in gastric cancer.37,38 In gastric mucosa of rats exposed to cigarette smoke, p53 is overexpressed.39 Upon p53 is activated, p53 target gene such as p21, a cyclin-dependent kinase inhibitor, regulates cell cycle arrest in G1 and induces apoptosis.40 Lycopene supplementation prevented changes in p53 expression in gastric mucosa of ferrets.39 Therefore, lycopene may protect against the development of gastric cancer by inhibiting p53-dependent apoptosis and correcting the unbalance of apoptosis and cell proliferation.
Over half of the world’s population is colonized with
As described above, in vitro and in vivo studies show anticancer effect of lycopene in gastric carcinogenesis. Many countries have implemented the clinical study of lycopene as the main component of tomato and tomato products An inverse association between tomato intake and gastric cancer incidence has been reported in some epidemiologic studies.
In China, meta-analysis study supports the negative relationship between tomato consumption and risk of gastric cancer.49 The risk of gastric cancer was significantly reduced in people consuming high lycopene compared to low intake group.49 High serum levels of lycopene were significantly associated with reduced risk of developing gastric cancer.50 In Finland cohort study, lycopene treatment did not affect the risk of gastric cardia cancer but decreased the risk of gastric noncardia cancer by <33%.51 In a case-control study in Uruguay, tomato intake was strong inverse associations with stomach cancer development.52 In Japan, plasma levels of lycopene were lower in
Lycopene from red fruits and vegetables has strong anticancer activity in gastric carcinogenesis. ROS have been implicated in the progression of several diseases including cancer. ROS cause severe cellular injury and promote tumor metastasis, angiogenesis, and invasion. As one of the most potent antioxidants, lycopene is effective in decreasing oxidative damage by activating antioxidant enzymes such as GSH, GPx and GST. Lycopene treatment inhibits cancer cell growth and induces apoptosis by suppressing ERK signaling pathway. Bcl-2 family and caspases are considered to be the most effective apoptotic regulators. Lycopene decreases Bcl-2 and increases Bax expression, which induce release of cytochrome C from mitochondria, leading to apoptosis. Lycopene treatment inhibits gastric cancer cell proliferation by increasing cell cycle arrest in G0?G1 phase. Moreover, lycopene prevents changes in p53 overexpression in gastric mucosa exposed to cigarette smoke.
Based on the studies, we propose a mechanism by which lycopene exerts protective effect against oxidative stress-mediated gastric carcinogenesis (Fig. 1). Smoking, inflammation, and
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