Transformed Drosophila Cells Evade Diet-Mediated Insulin Resistance through Wingless Signaling
Transformed Drosophila Cells Evade Diet-Mediated Insulin Resistance through Wingless Signaling
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DOI：
10.1016/j.cell.2013.06.030
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发表时间：
2013-08-01
期刊：
影响因子：
64.5
通讯作者：
Cagan, Ross L.
中科院分区：
文献类型：
--
作者：
Hirabayashi, Susumu;Baranski, Thomas J.;Cagan, Ross L.
患有代谢功能障碍（包括肥胖和糖尿病）的患者患特定癌症的风险增加。在这里，我们使用果蝇作为模型来探索饮食对肿瘤进展的影响。喂食果蝇高碳水化合物的饮食以前被证明会导致代谢功能障碍，包括高血糖症，高胰岛素血症和胰岛素抵抗。我们证明，高糖饮食也转换Ras/Src转化组织从局部生长与紧急转移的侵袭性肿瘤。虽然大多数组织显示胰岛素抵抗，Ras/Src肿瘤保留胰岛素途径的敏感性，增加输入葡萄糖的能力，并抵抗细胞凋亡。高糖增加了经典Wingless/Wnt途径的活性，从而上调胰岛素受体基因的表达以促进胰岛素敏感性。其结果是一个前馈电路，放大Ras/Src转化肿瘤内的饮食介导的恶性表型。通过针对该回路中的多个步骤合理应用药物组合，我们证明了组合药物干预治疗饮食增强的恶性肿瘤的潜力。
The risk of specific cancers increases in patients with metabolic dysfunction, including obesity and diabetes. Here, we use Drosophila as a model to explore the effects of diet on tumor progression. Feeding Drosophila a diet high in carbohydrates was previously demonstrated to direct metabolic dysfunction, including hyperglycemia, hyperinsulinemia, and insulin resistance. We demonstrate that high dietary sugar also converts Ras/Src-transformed tissue from localized growths to aggressive tumors with emergent metastases. Whereas most tissues displayed insulin resistance, Ras/Src tumors retained insulin pathway sensitivity, increased the ability to import glucose, and resisted apoptosis. High dietary sugar increased canonical Wingless/Wnt pathway activity, which upregulated insulin receptor gene expression to promote insulin sensitivity. The result is a feed-forward circuit that amplified diet-mediated malignant phenotypes within Ras/Src-transformed tumors. By targeting multiple steps in this circuit with rationally applied drug combinations, we demonstrate the potential of combinatorial drug intervention to treat diet-enhanced malignant tumors.