Zhu Zongjian, Jiang Weiqin, Thompson Henry J
Cancer Prevention Laboratory, Colorado State University, Fort Collins, 111 Shepardson, 1173 Campus Delivery, Fort Collins, CO 80523-1173, USA.
Carcinogenesis. 2003 Jul;24(7):1225-31. doi: 10.1093/carcin/bgg077. Epub 2003 May 9.
Increased secretion of adrenal cortical steroids may account in part for its cancer inhibitory activity of energy restriction (ER). To test this hypothesis, a study was conducted to determine the effects of dietary administration of corticosterone on the post-initiation stage of mammary carcinogenesis. Eighty-four female Sprague-Dawley rats were injected with 50 mg 1-methyl-1-nitrosourea/kg body wt (i.p.) at 21 days of age. One week later, animals were randomly divided into three groups and fed control diet, or that diet to which was added 200 or 400 mg corticosterone/kg. Diets were fed for 5 weeks after which the experiment was terminated. With increasing dietary corticosterone, a dose-dependent reduction in the incidence (P=0.03), multiplicity (P=0.003) and size (P<0.003) of mammary carcinomas was observed. Dietary administration of corticosterone also reduced plasma insulin-like growth factor-1 (IGF-1) and levels of IGF-1 receptor in mammary carcinomas (P<0.01). In order to investigate molecular mechanisms underlying anticancer activity, the levels and activities of cell cycle components involved in the G1-S transition were investigated in mammary carcinomas that emerged in treated animals. Levels of cyclin D1, cyclin E, cyclin-dependent kinase (CDK)-2 and CDK-4 were reduced in carcinomas from corticosterone treated rats; whereas, levels of cyclin-dependent kinase inhibitors (CKI) Kip1/p27 and Cip1/p21 were elevated. Binding of these CKIs to both the cyclin D1-CDK-4 complex and the cyclin E-CDK-2 complex were increased and the kinase activities of these complexes were reduced with increasing dietary corticosterone. These effects were consistent with those observed in response to ER in vivo and corticosterone exposure in vitro. Whereas the effects of exogenously administered corticosterone and ER had many similarities, the lower efficacy of corticosterone versus ER in inhibiting the carcinogenic process imply that changes in cortical steroid metabolism alone are unlikely to explain the cancer inhibitory activity of ER.
肾上腺皮质类固醇分泌增加可能部分解释了能量限制（ER）的癌症抑制活性。为了验证这一假设，进行了一项研究以确定饮食中给予皮质酮对乳腺癌发生起始后阶段的影响。84只雌性斯普拉格-道利大鼠在21日龄时腹腔注射50mg 1-甲基-1-亚硝基脲/千克体重。一周后，将动物随机分为三组，分别喂食对照饮食，或添加200或400mg皮质酮/千克的饮食。饮食喂养5周后终止实验。随着饮食中皮质酮含量的增加，观察到乳腺癌的发生率（P = 0.03）、肿瘤数量（P = 0.003）和大小（P < 0.003）呈剂量依赖性降低。饮食中给予皮质酮还降低了血浆胰岛素样生长因子-1（IGF-1）以及乳腺癌中IGF-1受体的水平（P < 0.01）。为了研究抗癌活性的分子机制，在接受治疗动物中出现的乳腺癌中研究了参与G1-S期转换的细胞周期成分的水平和活性。皮质酮处理大鼠的癌组织中细胞周期蛋白D1、细胞周期蛋白E、细胞周期蛋白依赖性激酶（CDK）-2和CDK-4的水平降低；而细胞周期蛋白依赖性激酶抑制剂（CKI）Kip1/p27和Cip1/p21的水平升高。随着饮食中皮质酮含量的增加，这些CKI与细胞周期蛋白D1-CDK-4复合物和细胞周期蛋白E-CDK-2复合物的结合增加，并且这些复合物的激酶活性降低。这些效应与体内ER反应和体外皮质酮暴露所观察到的效应一致。虽然外源性给予皮质酮和ER的效应有许多相似之处，但皮质酮相对于ER在抑制致癌过程中的效力较低，这意味着仅皮质类固醇代谢的变化不太可能解释ER的癌症抑制活性。
