Lycopene Supplementation Inhibits Lung Squamous Metaplasia

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http://cancerres.aacrjournals.org/cgi/content/abstract/63/12/3138

 

Cancer Research 63, 3138-3144, June 15, 2003]

© 2003 American Association for Cancer Research

 

 

Epidemiology and PreventionLycopene Supplementation Inhibits Lung Squamous

Metaplasia and Induces Apoptosis via Up-Regulating Insulin-like Growth

Factor-binding Protein 3 in Cigarette Smoke-exposed Ferrets1 Chun Liu, Fuzhi

Lian, Donald E. Smith, Robert M. Russell and Xiang-Dong Wang2

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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