Zhu Zongjian, Jiang Weiqin, McGinley John N, Price Jennifer M, Gao Bifeng, Thompson Henry J
Cancer Prevention Laboratory, Colorado State University, Fort Collins, Colorado 80523, USA.
Cancer Res. 2007 Dec 15;67(24):12018-25. doi: 10.1158/0008-5472.CAN-07-2834.
The objective of this study was to determine whether dietary energy restriction (DER) affects the pattern of gene expression in three interrelated energy metabolism pathways: glycolysis, gluconeogenesis, and the citric acid cycle. Mammary carcinogenesis was initiated by the i.p. injection of female Sprague-Dawley rats with 50 mg of 1-methyl-1-nitrosourea per kilogram of body weight. Five days following 1-methyl-1-nitrosourea administration, animals were fed ad libitum or 80% or 60% of the ad libitum intake. Epithelial cells were harvested from histologically confirmed adenocarcinomas (adenocarcinoma epithelial cell; ACEC) and uninvolved mammary gland (mammary gland epithelial cells; MGEC) via laser capture microdissection, whereas isolated RNA was arrayed on Affymetrix R230 2.0 genome chips. Principal components analysis revealed complete separation of the patterns of gene expression between ACEC versus MGEC. Further examination of the data set revealed an up-regulated pattern of expression in the ACEC of genes involved in glycolysis, whereas gluconeogenesis was suppressed. In general, genes involved in the citric acid cycle were not differentially expressed; however, pyruvate dehydrogenase expression was down-regulated and lactate dehydrogenase expression was increased in ACEC versus MGEC. Collectively, the observed patterns of expression were consistent with the Warburg effect. DER exerted no effect on the Warburg pattern of gene expression or on other aspects of these energy metabolism pathways. These findings imply that efforts to target the Warburg effect for cancer prevention are mechanistically distinct from those modulated by DER and provide a rationale for the combination of approaches that target basic defects in energy metabolism and energy-sensing pathways for the prevention of breast cancer.
本研究的目的是确定饮食能量限制（DER）是否会影响三个相互关联的能量代谢途径（糖酵解、糖异生和柠檬酸循环）中的基因表达模式。通过给雌性斯普拉格-道利大鼠腹腔注射每千克体重50毫克的1-甲基-1-亚硝基脲来引发乳腺癌。在给予1-甲基-1-亚硝基脲五天后，动物被给予自由采食或自由采食量的80%或60%。通过激光捕获显微切割从组织学确诊的腺癌（腺癌上皮细胞；ACEC）和未受累的乳腺（乳腺上皮细胞；MGEC）中收集上皮细胞，而分离的RNA则被排列在Affymetrix R230 2.0基因组芯片上。主成分分析显示ACEC与MGEC之间基因表达模式完全分离。对数据集的进一步检查发现，参与糖酵解的基因在ACEC中的表达呈上调模式，而糖异生则受到抑制。一般来说，参与柠檬酸循环的基因没有差异表达；然而，与MGEC相比，丙酮酸脱氢酶在ACEC中的表达下调，乳酸脱氢酶的表达增加。总体而言，观察到的表达模式与瓦伯格效应一致。DER对基因表达的瓦伯格模式或这些能量代谢途径的其他方面没有影响。这些发现意味着针对瓦伯格效应进行癌症预防的努力在机制上与DER调节的努力不同，并为将针对能量代谢和能量感知途径基本缺陷的方法结合起来预防乳腺癌提供了理论依据。
