Identification of molecular targets for dietary energy restriction prevention of skin carcinogenesis: An idea cultivated by Edward Bresnick
Identification of molecular targets for dietary energy restriction prevention of skin carcinogenesis: An idea cultivated by Edward Bresnick
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DOI：
10.1002/jcb.10741
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发表时间：
2004-02-01
影响因子：
4
通讯作者：
Liu, Y
中科院分区：
文献类型：
--
作者：
Birt, DF;Przybyszewski, J;Liu, Y
长期以来，人们一直认为膳食能量限制（DER）在许多动物模型中可以显着抑制致癌作用。最近和正在进行的流行病学研究证实了动物数据，证明了能量平衡，体育锻炼和肥胖在人类癌症中的重要性。Edward Bresnick博士在担任Eppley癌症研究所所长期间为作者的研究提供了这一重要研究领域的关键见解和关键方向。这些见解推动了这项研究，证明DER减少了小鼠皮肤中关键蛋白激酶C亚型的表达。最近的研究已经揭示了由DER抑制的下游事件，包括Raf-1、ERK 1、2和AP-1表达的肿瘤启动子激活的阻断。平行研究已经证明，小鼠皮肤癌发生中这些关键细胞信号传导事件的DER抑制依赖于完整的肾上腺，因为饲喂DER饮食的肾上腺切除小鼠没有降低肿瘤负荷或抑制信号传导并阻断AP-1活化，如在具有完整肾上腺的DER小鼠中观察到的。此外，在饮用水中给予皮质酮的肾上腺切除小鼠中，肿瘤发生和AP-1信号传导的DER抑制恢复。这表明在小鼠化学致癌方案中糖皮质激素在介导DER预防癌症中起主要作用。正在进行研究，通过评估对皮肤癌发生中关键基因的转录调控和表达的影响，进一步评估皮肤癌的DER调节机制。
Dietary energy restriction (DER) has long been known to strikingly inhibit carcinogenesis in many animal models. The animal data has been corroborated by recent and ongoing epidemiological studies demonstrating the importance of energy balance, physical exercise and obesity in human cancer. Dr. Edward Bresnick provided key insights into this important area of research and pivotal direction for the author's research while he served as Director of the Eppley Institute for Research in Cancer, Omaha, NE. These insights moved this research toward demonstrating that DER reduced the expression of key protein kinase C isoforms in mouse skin. More recent studies have uncovered downstream events that are inhibited by DER including blockage of tumor promoter activation of Raf-1, ERK 1,2 and AP-1 expression. Parallel studies have demonstrated the DER inhibition of these key cellular signaling events in mouse skin carcinogenesis are dependent upon an intact adrenal gland because adrenalectomized mice fed DER diet did not have reduced tumor burden or inhibited signaling and blocked AP-1 activation as was observed in DER mice with intact adrenal glands. in addition, the DER inhibition of tumorigenesis and AP-1 signaling was restored in adrenalectomized mice that were given corticosterone in the drinking water. This showed that in mice in the chemical carcinogenesis protocol glucocorticoid hormone plays a major role in mediating DER prevention of cancer. Studies are ongoing to further assess the mechanism of DER modulation of skin cancer by assessing impacts on transcriptional regulation and expression of genes that are critical in skin carcinogenesis.