RT Journal Article SR Electronic T1 Chronic IL-1 exposure drives LNCaP cells to evolve androgen and AR independence JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.04.21.054452 DO 10.1101/2020.04.21.054452 A1 H.C. Dahl A1 M. Kanchwala A1 S.E. Thomas-Jardin A1 A. Sandhu A1 P. Kanumuri A1 A.F. Nawas A1 C. Xing A1 C. Lin A1 D.E. Frigo A1 N.A. Delk YR 2020 UL http://biorxiv.org/content/early/2020/09/22/2020.04.21.054452.abstract AB Chronic inflammation promotes prostate cancer (PCa) initiation and progression. We previously reported that acute intereluekin-1 (IL-1) exposure represses androgen receptor (AR) accumulation and activity, providing a possible mechanism for IL-1-mediated development of androgen- and AR-independent PCa. Given that acute inflammation is quickly resolved, and chronic inflammation is, instead, co-opted by cancer cells to promote tumorigenicity, we set out to determine if chronic IL-1 exposure leads to similar repression of AR and AR activity observed for acute IL-1 exposure and to determine if chronic IL-1 exposure selects for androgen- and AR- independent PCa cells. We generated isogenic sublines from LNCaP cells chronically exposed to IL-1α or IL-1β. Cells were treated with IL-1α, IL-1β, TNFα or HS-5 bone marrow stromal cells conditioned medium to assess cell viability in the presence of cytotoxic inflammatory cytokines. Cell viability was also assessed following serum starvation, AR siRNA silencing and enzalutamide treatment. Finally, RNA sequencing was performed for the IL-1 sublines. MTT, RT-qPCR and western blot analysis show that the sublines evolved resistance to inflammation- induced cytotoxicity and intracellular signaling and evolved reduced sensitivity to siRNA- mediated loss of AR, serum deprivation and enzalutamide. Differential gene expression reveals that canonical AR signaling is aberrant in the IL-1 sublines, where the cells show constitutive PSA repression and basally high KLK2 and NKX3.1 mRNA levels and bioinformatics analysis predicts that pro-survival and pro-tumorigenic pathways are activated in the sublines. Our data provide evidence that chronic IL-1 exposure promotes PCa cell androgen and AR independence and, thus, supports CRPCa development.Competing Interest StatementThe authors have declared no competing interest.