Effect of energy restriction on cell cycle machinery in 1-methyl-1-nitrosourea-induced mammary carcinomas in rats.
Effect of energy restriction on cell cycle machinery in 1-methyl-1-nitrosourea-induced mammary carcinomas in rats.
复制标题
DOI：
--
复制
发表时间：
2003-03
期刊：
影响因子：
11.2
通讯作者：
Weiqin Jiang;Zongjian Zhu;H. Thompson
中科院分区：
文献类型：
--
作者：
Weiqin Jiang;Zongjian Zhu;H. Thompson
能量限制（ER）导致对化学诱导的乳腺癌发生的深刻抑制。ER的癌症抑制活性已被证明与该疾病过程的癌前和恶性阶段的较低细胞增殖速率相关。此外，在胰岛素样生长因子（IGF）-I的血浆浓度降低且血浆皮质酮水平伴随升高的动物中，发生致癌抑制和细胞增殖抑制。鉴于这两种激素在信号转导途径中的作用，尽管通过不同的调节机制，我们报告了一些实验，以确定在40%雌激素受体大鼠中发生的乳腺癌中是否可以检测到IGF-I和皮质酮血浆水平变化对细胞周期调控的假设效应，与自由进食的对照大鼠或40%雌激素受体大鼠相比，能量充足7天的ER大鼠（ER-REP）。通过免疫沉淀、蛋白质印迹和激酶活性测定的适当组合确定，发现ER显著降低了磷酸化视网膜母细胞瘤和E2 F-1的水平。（分别约为40%和75%; P < 0.01），细胞周期蛋白依赖性激酶（CDK）2（82%）和CDK 4（77%）减少ER癌中的激酶活性可能解释了所观察到的对视网膜母细胞瘤和E2 F-1的作用。ER癌中Cip 1/p21、Kip 1/p27及其与CDK 2复合蛋白的表达均显著升高（P < 0.01），cyclin E表达降低。另一方面，ER对CDK 4激酶活性的调节可能归因于对细胞周期蛋白D1的影响以及P16和P19与CDK 4结合的增加。ER诱导的大多数变化被ER-REP逆转。这些观察结果与ER发挥其深刻的癌症抑制活性的假设是一致的，部分是通过细胞周期机制的多方面调节，可能通过伴随的皮质酮和IGF-1代谢的变化，尽管其他激素和生长因子的作用不应被忽视。
Energy restriction (ER) results in a profound inhibition of chemically induced mammary carcinogenesis. The cancer inhibitory activity of ER has been shown to be associated with lower rates of cell proliferation during both premalignant and malignant stages of this disease process. Moreover, inhibition of carcinogenesis and suppression of cell proliferation occur in animals in which plasma concentrations of insulin-like growth factor (IGF)-I are reduced, and plasma corticosterone levels are increased concomitantly. Given the role of both hormones in signal transduction pathways that can modulate cell cycle progression, albeit via different regulatory mechanisms, we report experiments conducted to determine whether hypothesized effects of changes in plasma levels of IGF-I and corticosterone on cell cycle regulation could be detected in mammary carcinomas occurring in 40% ER rats in comparison to ad libitum fed control rats or 40% ER rats that were energy repleted for 7 days (ER-REP). As determined by appropriate combinations of immunoprecipitations, Western blots, and kinase activity assays, it was found that levels of phosphorylated retinoblastoma and E2F-1 were significantly reduced by ER (approximately 40 and 75%, respectively; P < 0.01), an effect that was partially reversed by ER-REP. Reductions in cyclin-dependent kinase (CDK)2 (82%) and CDK4 (77%) kinase activity in ER carcinomas were likely to account for the observed effects on retinoblastoma and E2F-1. Both Cip1/p21 and Kip1/p27 and levels of these proteins complexed with CDK2 were significantly elevated in ER carcinomas (P < 0.01), and levels of cyclin E were reduced. On the other hand, regulation of CDK4 kinase activity by ER was likely attributable to effects on cyclin D1 as well as increased binding of P16 and P19 to CDK4. The majority of changes induced by ER were reversed by ER-REP. These observations are consistent with the hypothesis that ER exerts its profound cancer inhibitory activity, in part, by multifaceted regulation of cell cycle machinery, possibly via concomitant changes in corticosterone and IGF-1 metabolism, although the role of other hormones and growth factors should not be dismissed.