Abstract
Inflammation drives prostate cancer (PCa) progression. While inflammation is a cancer hallmark, the underlying mechanisms mediating inflammation-induced PCa are still under investigation. Interleukin-1 (IL-1) is an inflammatory cytokine that promotes cancer progression, including PCa metastasis and castration resistance. We previously found that acute IL-1 exposure represses PCa androgen receptor (AR) expression concomitant with the upregulation of pro-survival proteins, causing de novo accumulation of castration-resistant PCa cells. However, acute inflammation is primarily anti-tumorigenic, while chronic inflammation is pro-tumorigenic. Thus, using the LNCaP PCa cell line as model, we found that PCa cells can evolve insensitivity to chronic IL-1 exposure, restoring AR and AR activity and acquiring castration resistance. In this paper we expanded our chronic IL-1 model to include the MDA-PCa-2b PCa cell line to investigate the response to acute versus chronic IL-1 exposure and to compare the gene expression patterns that evolve in the LNCaP and MDA-PCa-2b cells chronically exposed to IL-1. We chronically exposed MDA-PCa-2b cells to IL-1α or IL-1β for several months to establish sublines. Once established, we determined subline sensitivity to exogenous IL-1 using cell viability assay, RT-qPCR and western blot. RNA sequencing was performed for parental and subline cells and over representation analysis (ORA) for geneset enrichment of biological process/pathway was performed. MDA-PCa-2b cells repress AR and AR activity in response to acute IL-1 exposure and evolve insensitivity to chronic IL-1 exposure. While cell biological and molecular response to acute IL-1 signaling is primarily conserved in LNCaP and MDA-PCa-2b cells, including upregulation of NF-κB signaling and downregulation of cell proliferation, the LNCaP and MDA-PCa-2b cells evolve conserved and unique molecular responses to chronic IL-1 signaling that may promote or support tumor progression. Our chronic IL-1 subline models can be used to identify underlying molecular mechanisms that mediate IL-1-induced PCa progression.
Highlights
While cell biological and molecular response to acute IL-1 signaling is primarily conserved in LNCaP and MDA-prostate cancer (PCa)-2b cells, including upregulation of NF-κB signaling and downregulation of cell proliferation, the LNCaP and MDA-PCa-2b cells evolve conserved and unique molecular responses to chronic IL-1 signaling that may promote or support tumor progression
We have shown that IL-1 receptor antagonist (IL-1Ra) can attenuate bone marrow stromal cell paracrine-induced IL-1 signaling in PCa cell lines in vitro [19]
While acute IL-1 exposure represses androgen receptor (AR) accumulation and activity in MDA-PCa-2b parental cells, as observed for LNCaP [16], the chronically exposed subline cells have restored AR accumulation and activity (Figure 1C). These results demonstrate that chronic IL-1 exposure selects for MDA-PCa-2b cells that evolve insensitivity to exogenous IL-1
Summary
While inflammation is a cancer hallmark, the underlying mechanisms mediating inflammation-induced PCa are still under investigation. Interleukin-1 (IL-1) is an inflammatory cytokine that promotes cancer progression, including PCa metastasis and castration resistance. In this paper we expanded our chronic IL-1 model to include the MDA-PCa-2b PCa cell line to investigate the response to acute versus chronic IL-1 exposure and to compare the gene expression patterns that evolve in the LNCaP and MDA-PCa-2b cells chronically exposed to IL-1. While chronic inflammation in the tumor microenvironment is an established hallmark of cancer [6], the underlying mechanisms of inflammation-induced disease are not fully elucidated
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