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: 10292940
• 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 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292940
• 关键词: Adult; American; American Cancer Society; Animal Model; Binding; 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; 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.

大约35.5％的美国男性肥胖，肥胖与高级前列腺呈正相关 癌症，耐castration的前列腺癌和前列腺特异性死亡率。肥胖已经过去了 与活跃的前列腺癌患者患者病理进展的风险增加50％有关 监视。但是，肥胖与前列腺之间关联的基础机制 癌症的进展仍然是要填补的重要知识差距。众所周知，肥胖的人经常 开发2型糖尿病（T2D），胰岛素和炎性细胞因子的血液水平增加，例如 白介素17（IL-17）。我们以前已经证明，IL-17促进了马的发展 PTEN-NULL小鼠中的耐castration前列腺癌。我们的初步研究发现前列腺癌 与高脂饮食诱导的肥胖症小鼠相比 瘦的pten-null小鼠。我们已经证明，胰岛素通过 抑制糖原合酶激酶3（GSK3）。此外，我们最初发现GSK3与和 磷酸化在住宅T780处的IL-17受体A（IL-17RA），导致泛素化和蛋白酶体介导 IL-17RA的降解。在肥胖小鼠中，高胰岛素血症激活的磷酸肌醇3-激酶（PI3K）/Akt 在S21处的磷酸化GSK3α和S9处的GSK3β，从而抑制GSK3活性；随后，IL-17RA GSK3磷酸化降低，导致IL-17RA蛋白水平升高，然后增强 IL-17信号传导和多个IL-17下游基因的表达增加。这些发现表明IL- 17信号传导和胰岛素信号传导通过GSK3串扰，这是一种新型机制，肥胖驱动 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信号传导的固有抑制剂，以及具有T2D的肥胖症，高水平的胰岛素增强IL-17介导 通过抑制GSK3活性的反应，从而促进前列腺癌的进展。我们建议 通过实现以下三个特定目的来检验我们的中心假设：目标1）确定GSK3的角色 在调查IL-17在PTEN-NULL肥胖小鼠中的亲肿瘤功能时。我们将使用两种动物模型：a）我们将 用野生型IL-17RA创建GSK3α； PTEN和GSK3β； PTEN双敲除小鼠；我们希望找到减少 在GSK3的IL-17RA磷酸化中，IL-17RA降解的降低以及IL-17介导的增加 小鼠前列腺的炎症，导致前列腺癌入口的增加； b）我们将创建IL-17RA T779a敲蛋白突变体（IL-17raki/ki）小鼠不会对GSK3介导的IL-17RA的磷酸化反应 从而允许评估GSK3的IL-17独立函数；鼠标T779与人类T780同源 在IL-17RA上；我们预计比较GSK3α的前列腺癌的形成没有显着差异； 带有IL-17RA T779A突变的GSK3野生型PTEN-NULL小鼠的GSK3β； PTEN双敲除小鼠。目的 2）定义GSK3抑制IL-17信号传导的分子机制。我们将确定IL-17RA是否 GSK3在T780处的磷酸化需要主要的磷酸化，如果还有其他GSK3 IL-17RA上的磷酸化位点。目标3）评估GSK3/IL-17状态与前列腺之间的关联 肥胖/糖尿病男性的癌症。我们将在500个前列腺癌标本中评估GSK3/IL-17状态 身体体重正常，超重和肥胖症患者有或没有T2D；我们将评估协会 在GSK3/IL-17状态和临床变量之间。成功完成拟议的研究将 提供肥胖如何驱动前列腺癌进展的新型分子机制，这将显着 促进知识并揭示了预防和治疗前列腺癌的新目标。