Salt-inducible kinases mediate nutrient-sensing to link dietary sugar and tumorigenesis in Drosophila
Salt-inducible kinases mediate nutrient-sensing to link dietary sugar and tumorigenesis in Drosophila
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DOI：
10.7554/elife.08501.001
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发表时间：
2015-11-17
期刊：
影响因子：
7.7
通讯作者：
Cagan, Ross L.
中科院分区：
文献类型：
--
作者：
Hirabayashi, Susumu;Cagan, Ross L.
癌细胞需要过量的营养来支持其增殖，但癌细胞如何感知并促进营养有利条件下的生长仍不完全清楚。流行病学研究表明，肥胖是各种癌症的危险因素。之前已经证明，给果蝇喂食高糖饮食不仅会导致代谢缺陷，包括肥胖和生物体胰岛素抵抗，还会将Ras/Src激活的细胞转化为侵袭性肿瘤。在这里，我们证明，Ras/Src激活的细胞是敏感的河马信号通路的扰动。我们提供的证据表明，营养线索激活盐诱导激酶，导致海马途径下调Ras/Src激活的细胞。结果是Yorkie依赖性的Wingless信号传导增加，Wingless信号传导是在胰岛素抵抗环境中促进饮食增强的Ras/Src肿瘤发生的关键介质。通过这种机制，Ras/Src激活的细胞被定位为有效地响应营养信号，并确保肿瘤在营养丰富的条件下生长，包括肥胖。
Cancer cells demand excessive nutrients to support their proliferation but how cancer cells sense and promote growth in the nutrient favorable conditions remain incompletely understood. Epidemiological studies have indicated that obesity is a risk factor for various types of cancers. Feeding Drosophila a high dietary sugar was previously demonstrated to not only direct metabolic defects including obesity and organismal insulin resistance, but also transform Ras/Srcactivated cells into aggressive tumors. Here we demonstrate that Ras/Src-activated cells are sensitive to perturbations in the Hippo signaling pathway. We provide evidence that nutritional cues activate Salt-inducible kinase, leading to Hippo pathway downregulation in Ras/Src-activated cells. The result is Yorkie-dependent increase in Wingless signaling, a key mediator that promotes diet-enhanced Ras/Src-tumorigenesis in an otherwise insulin-resistant environment. Through this mechanism, Ras/Src-activated cells are positioned to efficiently respond to nutritional signals and ensure tumor growth upon nutrient rich condition including obesity.