Hyperinsulinemia enhances interleukin-17-induced inflammation to promote prostate cancer development in obese mice through inhibiting glycogen synthase kinase 3-mediated phosphorylation and degradation of interleukin-17 receptor.
Hyperinsulinemia enhances interleukin-17-induced inflammation to promote prostate cancer development in obese mice through inhibiting glycogen synthase kinase 3-mediated phosphorylation and degradation of interleukin-17 receptor.
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DOI：
10.18632/oncotarget.7296
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发表时间：
2016-03-22
期刊：
影响因子：
--
通讯作者：
You Z
中科院分区：
文献类型：
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作者：
Liu S;Zhang Q;Chen C;Ge D;Qu Y;Chen R;Fan YM;Li N;Tang WW;Zhang W;Zhang K;Wang AR;Rowan BG;Hill SM;Sartor O;Abdel-Mageed AB;Myers L;Lin Q;You Z
白介素 17 (IL-17) 在炎症、自身免疫性疾病和一些癌症中发挥着重要作用。肥胖者处于慢性炎症状态，血清中 IL-17、胰岛素和胰岛素样生长因子 1 (IGF1) 水平升高。这些因素如何导致慢性炎症状态，从而促进肥胖男性侵袭性前列腺癌的发展，目前尚不清楚。我们发现，在肥胖小鼠中，高胰岛素血症增强了 IL-17 诱导的下游促炎基因的表达，同时增加了 IL-17 受体 A (IL-17RA) 的水平，从而导致更具侵袭性的前列腺癌的发展。糖原合酶激酶 3 (GSK3) 在 T780 处与 IL-17RA 持续结合并磷酸化，导致 IL-17RA 泛素化和蛋白酶体介导的降解，从而抑制 IL-17 介导的炎症。与正常细胞相比，增殖性人前列腺癌细胞中 IL-17RA 磷酸化降低，而 IL-17RA 水平升高。胰岛素和 IGF1 通过抑制 GSK3 增强 IL-17 诱导的炎症反应，这在体外培养的细胞系和体内前列腺癌肥胖小鼠模型中得到了证明。这些发现揭示了肥胖炎症加剧以及与肥胖相关的侵袭性前列腺癌发展的潜在机制，表明靶向 GSK3 可能是预防和治疗前列腺癌（尤其是肥胖男性）中抑制 IL-17 介导的炎症的潜在治疗方法。
Interleukin-17 (IL-17) plays important roles in inflammation, autoimmune diseases, and some cancers. Obese people are in a chronic inflammatory state with increased serum levels of IL-17, insulin, and insulin-like growth factor 1 (IGF1). How these factors contribute to the chronic inflammatory status that promotes development of aggressive prostate cancer in obese men is largely unknown. We found that, in obese mice, hyperinsulinemia enhanced IL-17-induced expression of downstream proinflammatory genes with increased levels of IL-17 receptor A (IL-17RA), resulting in development of more invasive prostate cancer. Glycogen synthase kinase 3 (GSK3) constitutively bound to and phosphorylated IL-17RA at T780, leading to ubiquitination and proteasome-mediated degradation of IL-17RA, thus inhibiting IL-17-mediated inflammation. IL-17RA phosphorylation was reduced, while the IL-17RA levels were increased in the proliferative human prostate cancer cells compared to the normal cells. Insulin and IGF1 enhanced IL-17-induced inflammatory responses through suppressing GSK3, which was shown in the cultured cell lines in vitro and obese mouse models of prostate cancer in vivo. These findings reveal a mechanism underlying the intensified inflammation in obesity and obesity-associated development of aggressive prostate cancer, suggesting that targeting GSK3 may be a potential therapeutic approach to suppress IL-17-mediated inflammation in the prevention and treatment of prostate cancer, particularly in obese men.