Research Project: Molecular Targets of Tomato Carotenoids and their Metabolites in Cancer Prevention

Location: Jean Mayer Human Nutrition Research Center On Aging

Project Number: 8050-51000-096-002-S
Project Type: Non-Assistance Cooperative Agreement

Start Date: May 1, 2014
End Date: Apr 30, 2019

Objective:
LAB NAME: Nutrition and Cancer Biology 1: Determine the ability of carotenoid-enriched food, carotenoids, and apocarotenoids (carotenoid cleavage metabolites by beta-carotene 9’,10’-oxygenase, BCO2) to induce SIRT1 by regulating microRNAs for preventing obesity-related inflammatory responses and cancer development in liver and colon. 1.1: Determine the protective effects of tomato extract, lycopene and apolycopenoids against high-fat diet-induced inflammatory responses and tumorigenesis. 1.2: Investigate the ability of tomato carotenoid and apolycopenoids to modulate SIRT1 and its down-stream effectors as a unique mechanism for preventing inflammation and tumorigenesis. 1.3: Determine whether SIRT1 activity is required for the preventive action of tomato carotenoids and apolycopenoids. 1.4: Investigate the protective effect of beta-cryptoxanthin (BCX, a provitamin A carotenoid) against high sugar diet-induced NAFLD and liver cancer via gut/adipose/liver axis. 1.5: Determine the biological functions of intact BCX in absence of carotene cleavage enzymes beta-carotene 15,15’-oxygenase 1 (BCO1) and beta-carotene 9’, 10’-oxygenase (BCO2) double knock out (KO) mice. 1.6: Determine the SIRT1 activity as a molecular target for BCX protection against high sugar diet-induced NAFLD and liver cancer.

Approach:
LAB NAME: Nutrition and Cancer Biology We will use both C57BL/6J mice and specific genetically-altered carotenoid cleavage enzyme (beta-carotene 9’,10’-oxygenase, BCO2) knockout mice strains to determine whether high-fat diet-induced liver inflammation and tumorigenesis can be prevented by apo-10’-lycopenoid (lycopene cleavage metabolite by BCO2), lycopene or tomato extract supplementation. We will examine the effects of dietary tomato carotenoids on modulating sirtuin 1 (SIRT1, a key metabolic sensor that directly links environmental nutrient signals to amelioration of inflammation as well as tumor development secondary to high-fat diet-induced obesity) expression/activity and its down-stream effectors, as well as its regulation by microRNAs in liver, intestine, colon and adipose tissues. We will use sirt1y/y homozygous mice that ablates the SIRT1 catalytic activity, as compared with their corresponding wild-type littermates, to determine the contribution of the tomato carotenoids and their metabolites to SIRT1 signaling pathway in liver, colon and adipose tissues, thus leading to the prevention of diet-induced obesity associated inflammation and cancer development. We will conduct a study of anti-inflammation effects of BCX on high sugar diet induced inflammation on liver and adipose tissue in BCO1-/- and BCO2-/- double knockout mice. We will conduct a comparison study of effects of BCX vs. red pepper extract on high sugar diet inflammation on liver and adipose tissue in BCO1-/- and BCO2-/- double knockout mice. We will conduct a study of the BCX on high sugar diet-induced inflammation on liver and adipose tissue and its related SIRT1 signaling. We will conduct a comparison study of effects of BCX vs. red pepper extract on high sugar diet –induced inflammation on liver and adipose tissue and its related SIRT1 signaling. We will conduct an intervention study of BCX on insulin resistance, inflammation and hepatic carcinogenesis in both WT and sirt1y/y homozygous mice. We will conduct a comparison study of effects of BCX on inflammation on liver and adipose tissue and its related SIRT1 signaling (including its up-stream regulators, such as microRNA regulation).