Liu Chun, Lian Fuzhi, Smith Donald E, Russell Robert M, Wang Xiang-Dong
Nutrition and Cancer Biology Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts 02111, USA.
Cancer Res. 2003 Jun 15;63(12):3138-44.
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 Ser(136) and Ser(112) 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.
在人体研究中，番茄红素摄入量较高与肺癌风险较低相关。肺癌风险与血浆中较高水平的胰岛素样生长因子I（IGF-I）和/或较低水平的IGF结合蛋白3（IGFBP-3）有关。然而，关于番茄红素是否能通过调节IGF-I/IGFBP-3、细胞增殖和凋亡来抑制香烟烟雾诱导的肺癌发生，目前所知甚少。我们研究了低剂量（1.1毫克/千克/天，相当于人类摄入量15毫克/天）和高剂量（4.3毫克/千克/天，相当于人类摄入量60毫克/天）番茄红素补充剂对暴露或未暴露于香烟烟雾9周的雪貂血浆IGF-I/IGFBP-3水平、组织病理学变化、增殖细胞核抗原（PCNA）表达、BAD磷酸化和凋亡（半胱天冬酶3检测）的影响。我们发现，补充番茄红素并暴露于烟雾中的雪貂，其血浆IGFBP-3水平显著更高（P<0.01），IGF-I/IGFBP-3比值更低（P<0.01），相比之下，仅暴露于烟雾中的雪貂则不然。低剂量和高剂量的番茄红素补充剂均能显著抑制雪貂肺部烟雾诱导的鳞状化生和PCNA表达。在对照雪貂或仅补充番茄红素的雪貂肺部未发现鳞状化生或PCNA过表达。此外，与对照组相比，香烟烟雾暴露显著增加了雪貂肺部BAD在Ser(136)和Ser(112)位点的磷酸化，并显著降低了裂解的半胱天冬酶3水平。低剂量和高剂量的番茄红素补充剂均能预防香烟烟雾在雪貂肺部诱导的BAD磷酸化升高和凋亡下调。仅补充番茄红素的雪貂血浆和肺部中的番茄红素水平呈剂量依赖性增加。然而，补充番茄红素并暴露于烟雾中的雪貂血浆和肺部中的番茄红素水平均显著较低。此外，与仅补充番茄红素的雪貂相比（13-顺式异构体为20%，9-顺式异构体为14%），烟雾暴露增加了雪貂肺部番茄红素的顺式异构体（13-顺式异构体为26%，9-顺式异构体为22%）。总之，番茄红素可能通过上调IGFBP-3和下调BAD磷酸化来介导其对雪貂烟雾诱导的肺癌发生的保护作用，从而促进凋亡并抑制细胞增殖。
