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首页> 外文期刊>Oncogene >Renal tumours in a Tsc2(+/-) mouse model do not show feedback inhibition of Akt and are effectively prevented by rapamycin
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Renal tumours in a Tsc2(+/-) mouse model do not show feedback inhibition of Akt and are effectively prevented by rapamycin

机译：Tsc2（+/-）小鼠模型中的肾肿瘤不显示对Akt的反馈抑制，并且雷帕霉素可有效预防

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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 Ca 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.
机译：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激活哺乳动物雷帕霉素复合物 1 （mTORC1） 靶标。先前的研究表明，mTORC1 激活与 mTORC2 底物 Akt 的反馈抑制有关。这可能会限制 TSC 相关肿瘤的生长，但在使用 mTOR 抑制剂治疗后会导致肿瘤细胞存活的矛盾促进。然而，Akt/mTOR 信号转导尚未在 TSC 相关肿瘤中得到充分研究，并且不确定 mTOR 抑制是否可以预防 TSC 相关肾肿瘤发生。在这项研究中，我们使用 Tsc2（+/-） 小鼠模型研究了肾肿瘤中的 Akt/mTOR 信号传导，并测试了 mTOR 抑制是否可以预防肾肿瘤发生。我们发现所有肾脏病变，包括囊肿、腺瘤和癌，都表现出 Akt 和 mTORC1 的激活，这可以通过 Akt 和 mTOR 及其下游靶标的蛋白质表达和磷酸化增加来证明。蛋白激酶 Ca 在这些病变中也高度表达和磷酸化，与 mTORC2 的激活一致。令人惊讶的是，IRS蛋白的表达高度，与培养的Tsc2（-/-）小鼠胚胎成纤维细胞中的显着减少形成鲜明对比，这表明在mTORC1过度激活的Tsc相关肿瘤中可能发生Akt反馈抑制丧失的一种机制。雷帕霉素的长期治疗降低了正常肾组织中Akt和mTORC1的活性，并阻断了所有类型肾脏病变的发展。总之，与以前的研究相比，我们发现 Akt 信号传导在 Tsc 相关肾脏病变中不受抑制，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。

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