Castration‐induced prostate epithelial cell apoptosis results from targeted oxidative stress attack of M1142‐macrophages.

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]