Chronic IL-1 exposure drives LNCaP cells to evolve androgen and AR independence.
Haley C DahlMohammed KanchwalaShayna E Thomas-JardinAmrit SandhuPreethi KanumuriAfshan F NawasChao XingChenchu LinDaniel E FrigoNikki Ayanna DelkPublished in: PloS one (2020)
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.
Keyphrases
- prostate cancer
- gene expression
- induced apoptosis
- drug induced
- bone marrow
- oxidative stress
- cell cycle arrest
- liver failure
- rheumatoid arthritis
- stem cells
- south africa
- dna methylation
- cell proliferation
- machine learning
- cell therapy
- respiratory failure
- hepatitis b virus
- intensive care unit
- drug delivery
- deep learning
- hyaluronic acid
- cancer therapy
- data analysis
- big data