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

Abstract

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.

Targeting Th17‐IL‐17 Pathway in Prevention of Micro‐Invasive Prostate Cancer in a Mouse Model

“…Most studies focus on the Th17 effector cytokine IL‐17A. Recent studies using animal models of autochthonous cancer from many independent groups have demonstrated that the Th17 axis and IL‐17A promotes development of colon , skin , breast , prostate , lung , and pancreas cancer . Th17 cells and IL‐17A are believed to have protumorigenic roles; however, in some specific context, they may have antitumorigenic roles .…”

“…The primary antibodies used were: rabbit anti‐laminin (1:100 dilution, Sigma–Aldrich, St. Louis, MO); rabbit anti‐E‐cadherin (#3195, 1:200 dilution), anti‐β‐catenin (#8480, 1:200 dilution), anti‐ZO‐1(#8193, 1:100 dilution), anti‐Snail (#3879, 1:500 dilution), anti‐Slug (#9585, 1:50 dilution), and anti‐TCF8/ZEB1 (#3396, 1:100 dilution) (Cell Signaling Technology, Beverly, MA); goat anti‐HIF‐1α (Y‐15, sc‐12542, 1:50 dilution), rabbit anti‐VEGFA (A‐20, sc‐152, 1:200 dilution) (Santa Cruz Biotechnology, Dallas, TX); rabbit anti‐CD31 (Ab28364, 1:50 dilution) (Abcam, Cambridge, MA); anti‐Ki‐67 (1:200 dilution) (Millipore, Billerica, MA). IHC results were analyzed by semi‐quantitative analysis as previously described . TUNEL staining was performed using TACS.XL® Blue Label in Situ Apoptosis Detection Kit (Trevigen, Gaithersburg, MD) per the manufacturer's instructions.…”

Prohibitin in Adipose and Immune Functions

“…Likewise, it is also possible that estrogen has a similar role in the regulation of PHB functions in macrophages and dendritic cells such as cell proliferation, differentiation, and cytokine production, which is altered in the ovariectomized mice and results in tumor development. Alternatively, it is also possible that lymph node tumor development in the ovariectomized AdipoY114F-PHB mice is a consequence of hyperinsulinemia due to metabolic dysregulation because hyperinsulinemia is known to promote cancer development in mice [56]. Irrespective of the cascade of events involved in tumor development in these mice, these data suggest that obesity-associated metabolic and immune dysregulation have a central role in obesity-linked tumor development [53,54].…”

Stressed and Inflamed, Can GSK3 Be Blamed?

“…IL-17-induced signaling activates NF-κB and C/EBPδ and β, and both transcription factors are regulated by GSK3β and other mechanisms. GSK3β negatively regulates IL-17 signaling by phosphorylating both the downstream effector C/EBPβ (thereby decreasing downstream gene expression) [56-58] and the IL-17RA receptor, which triggers its degradation [59]. Altogether, GSK3β is central in the regulation of IL-17 by controlling both its production and its effectors.…”