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

Abstract

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.

Tumor‐Associated Macrophages (TAM) are recruited to the aging prostate epithelial lesions and become intermingled with basal cells

“…These features are consistent with the M2 and TAM phenotypes, respectively. Corroborating our findings, CD68+/iNOS‐ macrophages were also found in the rat VP on day 5 after castration, although without being positive for CD163 22,23 . The M2 phenotype observed in the present study is compatible with the morphology showing frequent engulfment of apoptotic cells by intraepithelial macrophages, which would indicate an active scavenging function involved in the clearance of apoptotic cells, an essential role for preventing the buildup of dangerous inflammation signals 40 .…”

“…Macrophages have also been shown to interact with epithelial cells in a rather complex manner, 5 secreting factors that promote mutagenic events, cellular proliferation and motility 16‐18 . In the prostate, aside from the presence of stromal and perivascular macrophages, these cells have long been reported within the epithelium after androgen withdraw induced by castration 19‐23 . These intraepithelial macrophages appear to phagocytize apoptotic epithelial cells (efferocytosis) and contribute to the remodeling of the regressing prostate 19,22 .…”

Transcriptional regulators and regulatory pathways involved in prostate gland adaptation to a hypoandrogen environment

“…For instance, remarkable reprogramming of immune system cells (Desai et al, 2004) and smooth muscle cells (Antonioli et al, 2004(Antonioli et al, , 2007 as well as reorganization of the extracellular matrix (Vilamaior et al, 2000) have been described and associated with a redefined functional state and immune barrier system. Additionally, we have reported the occurrence of desquamation as an additional phenomenon contributing to epithelial cell deletion (Rosa-Ribeiro et al, 2014a), and a relevant role for two macrophage subpopulations in both (a) the induction of epithelial cell death (Barbosa et al, 2019) and (b) the clearance of cell corpses and maintenance of the noninflammatory status (Silva et al, 2018).…”

Polarization, migration, and homotypical interactions among prostatic smooth muscle cells in a laminin 111‐rich extracellular matrix

“…Fundamentally, SMCs lose the homotypic contacts and become atrophic, while progressively accumulating extracellular matrix components (ECM), particularly collagen and elastin (Taboga et al, 2008; van den Hooff, 1988). These mutual changes have been implicated in tumor progression, mainly because of interferences with the normal epithelial–stromal communication set during development (Adur et al, 2016; Cunha, 1972; Cunha et al, 1983), under the master regulation by androgens (Barbosa et al, 2019; Bruni‐Cardoso et al, 2010; Kurita et al, 2001; Rosa‐Ribeiro et al, 2014). Accordingly, prostatic SMC phenotype is also affected by androgen deprivation (Antonioli et al, 2007; Gerdes et al, 1996).…”