The role of IL-17 in obesity-associated prostate cancer progression

IL-17 在肥胖相关前列腺癌进展中的作用

• 批准号: 10047293
• 负责人: Zongbing You
• 金额: --
• 依托单位: SOUTHEAST LOUISIANA VETERANS HEALTH CARE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-10-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10047293
• 关键词: Adult; American; American Cancer Society; Animal Model; Binding; Biological; Blood; Body Weight; Cancer Etiology; Cancer Patient; Cessation of life; Clinical; Development; Diabetes Mellitus; Diagnosis; Disease; Gene Expression; Genes; Glycogen Synthase Kinase 3; Healthcare; High Fat Diet; Hormones; Human; Hyperinsulinism; Incidence; Inflammation; Inflammatory; Insulin; Insulin Resistance; Insulin Signaling Pathway; Interleukin-17; Knock-in; Knock-in Mouse; Knock-out; Knockout Mice; Knowledge; Life; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Modeling; Molecular; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Overweight; Pathologic; Patients; Phosphatidylinositols; Phosphorylation; Phosphorylation Site; Phosphotransferases; Plasma; Prevalence; Prevention; Prostate; Prostate Cancer therapy; Proteins; Reporting; Research; Risk; Role; Signal Pathway; Signal Transduction; Specimen; Surveys; Testing; Thinness; Time; Ubiquitination; Veterans; base; cancer diagnosis; castration resistant prostate cancer; clinically significant; cytokine; diabetic; diet-induced obesity; epidemiology study; high risk; inhibitor/antagonist; insulin signaling; men; mortality; multicatalytic endopeptidase complex; mutant; novel; obese person; obesity risk; prostate cancer progression; prostate cancer risk; receptor; response

About 35.5% American men are obese and obesity has been positively associated with high-grade prostate cancer, castration-resistant prostate cancer, and prostate cancer-specific mortality. Obesity has been associated with a 50% increased risk of pathological progression in prostate cancer patients under active surveillance. However, the molecular mechanisms underlying the association between obesity and prostate cancer progression remain as a significant knowledge gap to be filled. It is known that obese people often develop type 2 diabetes (T2D) with increased blood levels of insulin and inflammatory cytokines such as interleukin-17 (IL-17). We have previously demonstrated that IL-17 promotes development of hormone-naïve and castration-resistant prostate cancer in Pten-null mice. Our preliminary studies found that prostate cancer formation rate was increased by approximately 82% in high-fat diet-induced obese Pten-null mice compared to lean Pten-null mice. We have demonstrated that insulin enhances IL-17-induced gene expression through inhibition of glycogen synthase kinase 3 (GSK3). Moreover, we have originally found that GSK3 binds to and phosphorylates IL-17 receptor A (IL-17RA) at residue T780, leading to ubiquitination and proteasome-mediated degradation of IL-17RA. In obese mice, hyperinsulinemia activated phosphoinositide 3-kinase (PI3K)/Akt to phosphorylate GSK3α at S21 and GSK3β at S9, thus inhibiting GSK3 activity; subsequently, IL-17RA phosphorylation by GSK3 is reduced, resulting in increased levels of IL-17RA protein, followed by enhanced IL-17 signaling and increased expression of multiple IL-17 downstream genes. These findings suggest that IL- 17 signaling and insulin signaling crosstalk via GSK3, which is a novel mechanism by which obesity drives prostate cancer progression. Based on these findings, we have formulated a central hypothesis that GSK3 is an intrinsic inhibitor of IL-17 signaling, and in obesity with T2D, high levels of insulin enhance IL-17-mediated responses through inhibiting GSK3 activities, thereby promoting prostate cancer progression. We propose to test our central hypothesis through achieving the following three specific aims: Aim 1) Determine GSK3’s role in regulating IL-17’s pro-tumor function in Pten-null obese mice. We will use two animal models: a) we will create Gsk3α;Pten and Gsk3β;Pten double knockout mice with wild-type IL-17ra; we expect to find a decrease in IL-17RA phosphorylation by GSK3, a decrease in IL-17RA degradation, and an increase in IL-17-mediated inflammation in mouse prostate, resulting in an increase in prostate cancer incidence; b) we will create IL-17ra T779A knockin mutant (IL-17raKI/KI) mice that will not respond to GSK3-mediated phosphorylation of IL-17RA, thus allowing assessment of IL-17-independent functions of GSK3; mouse T779 is homologous to human T780 on IL-17RA; we expect to find no significant differences in prostate cancer formation comparing Gsk3α;Pten and Gsk3β;Pten double knockout mice with Gsk3 wild-type Pten-null mice with IL-17RA T779A mutation. Aim 2) Define the molecular mechanisms by which GSK3 inhibits IL-17 signaling. We will determine if IL-17RA phosphorylation at T780 by GSK3 requires a primed phosphorylation and if there are other GSK3 phosphorylation sites on IL-17RA. Aim 3) Assess the association between GSK3/IL-17 status and prostate cancer in obese/diabetic men. We will assess GSK3/IL-17 status in 500 prostate cancer specimens from patients with normal body weight, overweight, and obesity, with or without T2D; we will assess the associations between GSK3/IL-17 status and the clinical variables. Successful completion of the proposed studies will provide novel molecular mechanisms of how obesity drives prostate cancer progression, which will significantly advance the knowledge and reveal new targets in the prevention and treatment of prostate cancer.

约35.5%的美国男性肥胖，肥胖与高级别前列腺癌呈正相关 癌症、耐去势前列腺癌和前列腺癌特有的死亡率。肥胖症一直以来 活动状态下前列腺癌患者的病理进展风险增加50% 监视系统。然而，肥胖症和前列腺癌之间联系的分子机制 癌症进展仍然是一个需要填补的重大知识空白。众所周知，肥胖的人经常 发生2型糖尿病(T2D)，血液中胰岛素和炎性细胞因子水平升高，如 白介素17(IL-17)。我们先前已经证明，IL-17促进了荷尔蒙-幼稚的发展 以及Pten零基因小鼠中耐去势的前列腺癌。我们的初步研究发现前列腺癌 与对照组相比，高脂饮食诱导的肥胖小鼠的形成率增加了约82% 瘦Pten基因缺失的小鼠。我们已经证明，胰岛素通过增强IL-17诱导的基因表达 抑制糖原合成酶激酶3(GSK3)。此外，我们最初发现GSK3与AND结合 使IL-17受体A(IL-17RA)在T780残基上磷酸化，导致泛素化和蛋白酶体介导 IL-17RA的降解。在肥胖小鼠中，高胰岛素血症激活了磷脂酰肌醇3-激酶(PI3K)/Akt 在S21使Gsk3α磷酸化，在S9使Gsk3β磷酸化，从而抑制Gsk3活性；随后，IL-17RA GSK3的磷酸化水平降低，导致IL-17RA蛋白水平上升，随后增强 IL-17信号转导和多个IL-17下游基因表达增加。这些发现表明，IL-1 17信号和胰岛素信号串扰通过GSK3，这是一种肥胖驱动的新机制 前列腺癌的进展。基于这些发现，我们提出了一个中心假设，即GSK3是 IL-17信号的内在抑制，在肥胖伴T2D时，高水平的胰岛素增强了IL-17介导的 通过抑制GSK3活性作出反应，从而促进前列腺癌的进展。我们建议 通过实现以下三个具体目标来验证我们的中心假设：目标1)确定GSK3的S角色 调节IL-17‘S对Pten基因缺失肥胖小鼠促肿瘤作用的研究我们将使用两个动物模型：a)我们将 用野生型IL-17ra创建Gsk3α；pTEN和Gsk3β；pten双基因敲除小鼠；我们预计会发现减少 在GSK3对IL-17RA的磷酸化过程中，IL-17RA的降解减少，而IL-17介导的降解增加 小鼠前列腺炎症，导致前列腺癌发病率增加；b)我们将产生IL-17ra 对GSK3介导的IL-17RA磷酸化无反应的T779A敲门突变(IL-17raKI/Ki)小鼠， 因此，可以评估GSK3的IL-17非依赖性功能；小鼠T779与人类T780同源 关于IL-17RA；我们预计在前列腺癌的形成方面与GSK3α；Pten相比没有显著差异 和Gsk3β；Pten双基因敲除小鼠，携带IL-17RA T779A突变的Gsk3野生型Pten缺失小鼠。目标 2)明确GSK3抑制IL-17信号转导的分子机制。我们将确定IL-17RA是否 GSK3在T780处的磷酸化需要启动的磷酸化，如果有其他GSK3 IL-17RA上的磷酸化位点。目的3)评估GSK3/IL-17状态与前列腺癌的关系 肥胖/糖尿病男性的癌症。我们将评估500例前列腺癌标本中GSK3/IL-17的状态 体重正常、超重和肥胖的患者，无论是否有T2D；我们将评估它们之间的关联 GSK3/IL-17状态与临床变量之间的关系。成功完成拟议的研究将 为肥胖如何推动前列腺癌进展提供了新的分子机制，这将显著 提升前列腺癌防治知识，揭示前列腺癌防治新靶点。