期刊
ONCOTARGET
卷 7, 期 12, 页码 13651-13666出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.7296
关键词
hyperinsulinemia; obesity; prostate cancer; interleukin-17; GSK3
资金
- National Institutes of Health [R01CA174714, P20GM103518]
- Department of Defense [W81XWH-14-1-0050, W81XWH-14-1-0149, W81XWH-14-1-0458, W81XWH-15-1-0444]
- Developmental Fund of Tulane Cancer Center (TCC)
- Louisiana Cancer Research Consortium (LCRC) Fund
- Tulane's Institute of Integrated Engineering for Health and Medicine (TI2EHM)
- National Institute on Minority Health and Health Disparities (NIMHD)/NIH [2G12MD007595]
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据