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

// Sen Liu 1, * , Qiuyang Zhang 1, * , Chong Chen 1 , Dongxia Ge 1 , Yine Qu 1 , Rongyi Chen 2 , Yi-Ming Fan 2 , Nan Li 2 , Wendell W. Tang 3 , Wensheng Zhang 4 , Kun Zhang 4 , Alun R. Wang 5 , Brian G. Rowan 1, 6, 7 , Steven M. Hill 1, 6 , Oliver Sartor 6, 8, 9 , Asim B. Abdel-Mageed 6, 8 , Leann Myers 10 , Qishan Lin 11 , Zongbing You 1, 6, 7, 12 1 Department of Structural and Cellular Biology, Tulane University, New Orleans, LA 70112, USA 2 Department of Dermatology, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, China 3 Department of Pathology, Ochsner Clinic Foundation, New Orleans, LA 70130, USA 4 Department of Computer Science and Biostatistics Facility of RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA 70125, USA 5 Department of Pathology and Laboratory Medicine, Tulane University, New Orleans, LA 70112, USA 6 Tulane Cancer Center, Louisiana Cancer Research Consortium, Tulane University, New Orleans, LA 70112, USA 7 Tulane Center for Stem Cell Research and Regenerative Medicine, Tulane University, New Orleans, LA 70112, USA 8 Department of Urology, Tulane University, New Orleans, LA 70112, USA 9 Department of Medicine, Tulane University, New Orleans, LA 70112, USA 10 Department of Biostatistics and Bioinformatics, Tulane University, New Orleans, LA 70112, USA 11 Proteomics/Mass Spectrometry Facility, University at Albany, Rensselaer, NY 12144, USA 12 Department of Orthopaedic Surgery and Tulane Center for Aging, Tulane University, New Orleans, LA 70112, USA * These authors contributed equally to this work Correspondence to: Zongbing You, e-mail: zyou@tulane.edu Keywords: hyperinsulinemia, obesity, prostate cancer, interleukin-17, GSK3 Received: December 02, 2015      Accepted: January 29, 2016      Published: February 10, 2016 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.