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Prostate development and function are regulated by androgens. Epithelial cell apoptosis in response to androgen deprivation is caspase‐9‐dependent and peaks at Day 3 after castration. However, isolated epithelial cells survive in the absence of androgens. Znf142 showed an on‐off expression pattern in intraepithelial CD68‐positive macrophages, with the on‐phase at Day 3 after castration. Rats treated with gadolinium chloride to deplete macrophages showed a significant drop in apoptosis, suggesting a causal relationship between macrophages and epithelial cell apoptosis. Intraepithelial M1‐polarization was also limited to Day 3, and the inducible nitric oxide synthase (iNOS) knockout mice showed significantly less apoptosis than wild‐type controls. The epithelial cells showed focal DNA double‐strand breaks (DSB), 8‐oxoguanine, and protein tyrosine‐nitrosylation, fingerprints of exposure to peroxinitrite. Cultured epithelial cells induced M1‐polarization and showed focal DSB and underwent apoptosis. The same phenomena were reproduced in LNCaP cells cocultured with Raw 264.7 macrophages. In conclusion, the M1 142‐macrophage (named after Znf142) attack causes activation of the intrinsic apoptosis pathway in epithelial cells after castration. [ABSTRACT FROM AUTHOR]

Background & Aims: Epidemiology studies have shown that obesity increases risk for colorectal cancer (CRC). We investigated the contribution of obesity-induced increases in levels of tumor necrosis factor (TNF)-α and hyperinsulinemia to the development of CRC in mice. Methods: Lean and obese mice (C57BL6/J and ob/ob) were given a combination of azoxymethane and dextran sulfate sodium, which led to the development of CRC; lean and obese severe combined immunodeficient mice were injected with HT-29 cells. We analyzed the roles of TNF-α and insulin in the development of obesity-mediated CRC using immunoblot, immunohistochemical, and apoptosis assays. Results: Genetic- and diet-induced obesity increased the incidence and size of tumors that developed after administration of azoxymethane and dextran sulfate sodium, compared with lean mice. HT-29 xenograft tumors grew more rapidly in obese than lean mice. Neutralization of TNF-α reduced activation of c-Jun N-terminal kinase, IκB kinase, and the phosphatidylinositol 3-kinase–Akt–mammalian target of rapamycin signaling pathway; it also reduced the growth and development of tumors in obese mice. Reducing levels of insulin levels had no effect on tumor growth in obese mice. Conclusions: TNF-α contributes to colon tumor growth in obese mice. Reagents that inhibit TNF-α might prevent the development or progression of CRC in obese individuals. [ABSTRACT FROM AUTHOR]

Prostate growth and physiology are regulated by steroid hormones and modulated by multiple endocrine factors. We investigated the action of insulin on the tissue organization and kinetics of epithelial cells in the rat ventral prostate (VP) in response to castration up to 120 hours after surgery by using an acute protocol of alloxan-induced diabetes. Diabetes caused a reduction in volume density (V(v%)) and volume of the epithelium. The effects of castration on the epithelium were accelerated in the diabetic animals, as determined by changes in V(v%) and volume. The smooth muscle cells became atrophic and apparently relaxed in response to castration, in contrast to the spinous aspect observed in nondiabetic castrated rats. Counting of apoptotic nuclei in the epithelium showed the classical apoptosis peak at 72 hours in nondiabetic rats and an advance of the apoptosis peak to 48 hours after castration in diabetic rats. Insulin restored the time of the peak to 72 hours. These results were confirmed after immunostaining for cleaved caspase-3 and suggest a survival and antiapoptotic effect on VP epithelial cells in both the presence and absence of androgen stimulation. This idea is supported by the observation that insulin also reduced the overall rate of apoptosis at all experimental points analyzed before and after castration.