Institute of Medical Genetics, Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.
Section of Pathology, Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.
Oncogene. 2015 Feb 12;34(7):922-31. doi: 10.1038/onc.2014.17. Epub 2014 Mar 17.
Tuberous sclerosis (TSC) is an inherited syndrome in which tumours in multiple organs are characterised by activation of mammalian target of rapamycin complex 1 (mTORC1). Previous work suggests that mTORC1 activation is associated with feedback inhibition of Akt, a substrate of mTORC2. This could limit TSC-associated tumour growth but lead to paradoxical promotion of tumour cell survival upon treatment with mTOR inhibitors. However, Akt/mTOR signalling has not been fully investigated in TSC-associated tumours and it has been uncertain whether mTOR inhibition can prevent TSC-associated renal tumourigenesis. In this study, we investigated Akt/mTOR signalling in renal tumours using a Tsc2(+/-) mouse model and tested whether mTOR inhibition could prevent renal tumourigenesis. We found that all renal lesions including cysts, adenomas and carcinomas exhibited activation of both Akt and mTORC1 as evidenced by increased protein expression and phosphorylation of Akt and mTOR and their downstream targets. Protein kinase Cα was also highly expressed and phosphorylated in these lesions, consistent with activation of mTORC2. Surprisingly, IRS proteins were highly expressed, in contrast to a striking decrease seen in cultured Tsc2(-/-) mouse embryonic fibroblasts, suggesting one mechanism through which loss of feedback inhibition of Akt may occur in mTORC1 hyperactivated Tsc-associated tumours. Long-term treatment with rapamycin reduced both Akt and mTORC1 activity in normal kidney tissues and blocked the development of all types of renal lesions. In conclusion, in contrast to previous studies, we found that Akt signalling is not inhibited in Tsc-associated renal lesions and that by partially inhibiting the Akt/mTOR pathway, rapamycin is highly effective in preventing Tsc-associated tumours.
结节性硬化症（TSC）是一种遗传性综合征，其中多个器官的肿瘤的特征是哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）的激活。先前的工作表明，mTORC1 的激活与 Akt 的反馈抑制有关，Akt 是 mTORC2 的底物。这可能会限制 TSC 相关肿瘤的生长，但在使用 mTOR 抑制剂治疗时会导致肿瘤细胞存活的反常促进。然而，Akt/mTOR 信号通路在 TSC 相关肿瘤中尚未得到充分研究，也不确定 mTOR 抑制是否可以预防 TSC 相关的肾肿瘤发生。在这项研究中，我们使用 Tsc2(+/-)小鼠模型研究了肾脏肿瘤中的 Akt/mTOR 信号通路，并测试了 mTOR 抑制是否可以预防肾肿瘤发生。我们发现，所有的肾脏病变，包括囊肿、腺瘤和癌，都表现出 Akt 和 mTORC1 的激活，这表现为 Akt 和 mTOR 的蛋白表达和磷酸化增加及其下游靶标。蛋白激酶 Cα 也在这些病变中高度表达和磷酸化，这与 mTORC2 的激活一致。令人惊讶的是，IRS 蛋白高度表达，与在培养的 Tsc2(-/-)小鼠胚胎成纤维细胞中观察到的明显减少形成鲜明对比，这表明 Akt 反馈抑制丧失可能发生在 mTORC1 过度激活的 TSC 相关肿瘤中的一种机制。长期使用雷帕霉素可降低正常肾脏组织中的 Akt 和 mTORC1 活性，并阻止所有类型的肾脏病变的发展。总之，与先前的研究相反，我们发现 Akt 信号在 TSC 相关的肾脏病变中没有被抑制，并且通过部分抑制 Akt/mTOR 通路，雷帕霉素在预防 TSC 相关肿瘤方面非常有效。
