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Lycopene Supplementation Inhibits Lung Squamous Metaplasia and Induces Apoptosis via Up-Regulating Insulin-like Growth Factor-binding Protein 3 in Cigarette Smoke-exposed Ferrets¹

Nutrition and Cancer Biology Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts 02111

Higher intake of lycopene is related to a lower risk of lung cancer in human studies. Lung cancer risk is associated with higher plasma levels of insulin-like growth factor I (IGF-I) and/or lower levels of IGF-binding protein 3 (IGFBP-3). However, little is known regarding whether lycopene can inhibit cigarette smoke-induced lung carcinogenesis through modulation of IGF-I/IGFBP-3, cell proliferation, and apoptosis. We investigated the effects of lycopene supplementation at a low dose (1.1 mg/kg/day, which is equivalent to an intake of 15 mg/day in humans) and a high dose (4.3 mg/kg/day, which is equivalent to 60 mg/day in humans) on plasma IGF-I/IGFBP-3 levels, histopathological changes, proliferating cellular nuclear antigen (PCNA) expression, BAD phosphorylation, and apoptosis (caspase 3 assay) in lungs of ferrets with or without cigarette smoke exposure for 9 weeks. We found that ferrets supplemented with lycopene and exposed to smoke had significantly higher plasma IGFBP-3 levels (P < 0.01) and a lower IGF-I/IGFBP-3 ratio (P < 0.01) than ferrets exposed to smoke alone. Both low- and high-dose lycopene supplementations substantially inhibited smoke-induced squamous metaplasia and PCNA expression in the lungs of ferrets. No squamous metaplasia or PCNA overexpression were found in the lungs of control ferrets or those supplemented with lycopene alone. Furthermore, cigarette smoke exposure greatly increased BAD phosphorylation at both Ser¹³⁶ and Ser¹¹² and significantly decreased cleaved caspase 3 in the lungs of ferrets, as compared with controls. The elevated phosphorylation of BAD and down-regulated apoptosis induced by cigarette smoke in the lungs of ferrets was prevented by both low- and high-dose lycopene supplementations. Lycopene levels were increased in a dose-dependent manner in both plasma and lungs of ferrets supplemented with lycopene alone. However, lycopene levels were markedly lower in both plasma and lungs of ferrets supplemented with lycopene and exposed to smoke. Furthermore, smoke exposure increased cis isomers (26% for 13-cis and 22% for 9-cis) of lycopene in the lungs of ferrets, compared with that of ferrets supplemented with lycopene alone (20% for 13-cis and 14% for 9-cis). In conclusion, lycopene may mediate its protective effects against smoke-induced lung carcinogenesis in ferrets through up-regulating IGFBP-3 and down-regulating phosphorylation of BAD, which promote apoptosis and inhibit cell proliferation.

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