Department of Surgery, University Hospital Regensburg, University of Regensburg, Regensburg, Germany.
Oncogene. 2010 Mar 11;29(10):1553-60. doi: 10.1038/onc.2009.435. Epub 2009 Dec 7.
The adenomatous polyposis coli (APC) gene is mutated in familial adenomatous polyposis. Mice with a heterozygous APC(Min) mutation develop multiple intestinal neoplasia (Min) leading to premature death. Early in colorectal carcinogenesis, APC(Min/+) mice show enhanced Akt-mammalian target of rapamycin (mTOR) signaling, which is paralleled by upregulation of oncogenic K(+) channels. In this study, we tested the effect of mTOR inhibition with rapamycin on tumor formation in APC(Min/+) mice and evaluated ion channel regulation. We found that continuous long-term rapamycin treatment of APC(Min/+) mice dramatically inhibits intestinal neoplasia. Moreover, although untreated APC(Min/+) mice lose weight, experience intestinal bleeding and succumb to multiple neoplasia by 22.3+/-1.4 weeks of age, mice treated with rapamycin maintain stable weight and survive long term (39.6+/-3.4 weeks), with more than 30% surviving >1 year. Impressively, abnormalities in colonic electrolyte transport typical for APC(Min/+) mice are abolished, along with the suppression of epithelial Na(+) channel (ENaC) and oncogenic K(+) ion channels BK, Elk1 and Erg1, both functionally and at mRNA levels. These results show that continuous prophylaxis by rapamycin markedly inhibits the development of APC mutation-related polyposis, and suggest a novel contributing mechanism of action through the blockade of intestinal oncogenic ion channels.
腺瘤性结肠息肉病（APC）基因在家族性腺瘤性息肉病中发生突变。杂合 APC(Min)突变的小鼠会发展出多发性肠肿瘤（Min），导致早逝。在结直肠癌的早期，APC(Min/+)小鼠表现出增强的 Akt-雷帕霉素靶蛋白（mTOR）信号，这与致癌性 K(+)通道的上调平行。在这项研究中，我们测试了雷帕霉素对 APC(Min/+)小鼠肿瘤形成的 mTOR 抑制作用，并评估了离子通道的调节。我们发现，持续长期雷帕霉素治疗 APC(Min/+)小鼠可显著抑制肠肿瘤形成。此外，尽管未治疗的 APC(Min/+)小鼠体重减轻，经历肠道出血，并在 22.3+/-1.4 周龄时死于多发性肿瘤，但用雷帕霉素治疗的小鼠保持稳定的体重并长期存活（39.6+/-3.4 周），超过 30%的小鼠存活时间超过 1 年。令人印象深刻的是，APC(Min/+)小鼠中典型的结肠电解质转运异常被消除，同时抑制上皮钠通道（ENaC）和致癌性 K(+)离子通道 BK、Elk1 和 Erg1，无论是在功能上还是在 mRNA 水平上。这些结果表明，雷帕霉素的持续预防可显著抑制 APC 突变相关息肉病的发展，并提示通过阻断肠道致癌性离子通道发挥新的作用机制。
