Loss of Nkx3.1 Expression in Bacterial Prostatitis

Abstract

NKX3.1 is a homeodomain protein that functions as a dosage sensitive prostate-specific transcription factor. Diminished NKX3.1 expression is associated with prostate epithelial cell proliferation in vitro and with increasing Gleason grade in patient samples. Mouse Nkx3.1 also functions as a negative regulator of prostate cell growth in prostate cancer models. Identifying biological and environmental factors that modulate NKX3.1 accumulation is therefore central to efforts aimed at elucidating prostate growth control mechanisms. To determine the effect of inflammation on Nxk3.1 accumulation, bacterial prostatitis was induced by intraurethral inoculation of a uropathogenic E. coli strain in mice. Nkx3.1 expression was profoundly reduced in infected prostate lobes and correlated with increased expression of a proliferation marker. Androgen receptor levels were also reduced in concert with Nkx3.1, and a marked increase in the basal cell marker p63 was observed. Analyses of the inflammatory infiltrate revealed a classic acute inflammatory response that attained characteristics of a chronic state within fourteen days postinoculation. Comparison of the four prostate lobes revealed clear differences in the extent of inflammation. These data demonstrate that acute inflammation in response to a bacterial agent in the prostate is associated with a significant diminution in the level of a key regulator of prostate cell proliferation. These observations provide a plausible mechanism whereby prostate inflammation may establish a local environment conducive to epithelial cell growth.

Non-Cell-Autonomous Regulation of Prostate Epithelial Homeostasis by Androgen Receptor

“…We demonstrate directly in vivo that attenuation of luminal epithelial AR signaling is capable of inducing prostate inflammation. On the other hand, inflammation has also been shown to suppress expression of AR and critical enzymes for testosterone metabolism (Debelec-Butuner et al, 2014; Khalili et al, 2010; Shinohara et al, 2013; Simons et al, 2014; Vignozzi et al, 2012a). Together, these results suggest a mutual induction between prostate inflammation and reduced luminal AR expression and imply the existence of a vicious cycle of prostate inflammation enforced by declining epithelial AR signaling.…”

NKX3.1 Suppresses TMPRSS2–ERG Gene Rearrangement and Mediates Repair of Androgen Receptor–Induced DNA Damage

“…Inflammation is accompanied by generation of reactive oxygen species that increases the chance of DNA damage. In regions of prostatic inflammation NKX3.1 protein is lost, precisely in the regions of the gland where it may be most needed to enhance the DNA damage response (5, 36). NKX3.1 protein loss would predispose to genetic rearrangements and DNA damage caused by reactive oxygen species generated by inflammation.…”

Nkx3.1 controls the DNA repair response in the mouse prostate

“…It is in these regions where inflammatory cells increase the formation of reactive oxygen species that cytokines are generated as well. Loss of NKX3.1 precisely in regions of inflammatory atrophy is mediated by inflammatory cytokines and thereby results in enhanced vulnerability to mutagenesis 20, 21, 22. Thus, the physiologic aging process is accompanied by changes that increase the likelihood of mutagenesis due to regional reductions in NKX3.1 at sites of inflammation.…”