TNF Is Necessary for Castration-Induced Prostate Regression, Whereas TRAIL and FasL Are Dispensable

Department of Pathology and Laboratory Medicine, School of Medicine, University of California, Irvine, California 92697-4800, USA.
The Journal of Clinical Endocrinology and Metabolism (Impact Factor: 6.21). 03/2011; 96(3):873. DOI: 10.1210/me.2010-0312
Source: PubMed


TNF, a proinflammatory and immune-regulatory cytokine, is a potent apoptotic stimulus in vitro. However, there have been few examples of a physiologic role for TNF-induced apoptosis in vivo. Here, we describe a novel role for TNF in prostate epithelial cell apoptosis after androgen withdrawal. Employing high-resolution serial magnetic resonance imaging to measure mouse prostate volume changes over time, we demonstrate that the extent of castration-induced prostate regression is significantly reduced in mice null for either the Tnf or Tnfr1 genes but not mice deficient for TNF-related apoptosis-inducing ligand or Fas signaling. Wild-type mice receiving soluble TNF (sTNF) receptor 2 (to bind TNF and block signaling) before castration exhibit an identical reduction of prostate regression. Together, these data indicate that uniquely among known extrinsic death signals, TNF is required for castration-induced prostate regression. Additionally, membrane-bound TNF protein and stromal cell specific TNF mRNA levels increase in rat prostate after castration. This is consistent with a paracrine role for TNF in prostate regression. When injected into the peritoneum of Tnf(-/-) mice at the time of castration, sTNF restores normal levels of prostate regression. However, wild-type mice receiving sTNF in the absence of castration do not exhibit prostate regression, indicating that TNF alone is not sufficient but acts in the context of additional castration-induced signals. These findings support a physiologic role for TNF in prostate regression after androgen withdrawal. Understanding this role may lead to novel therapies for prostate cancer.

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Available from: Kent L Nastiuk
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    • "Emerging evidence indicates that TNF has key roles in both castration-induced regression of the normal prostate, as well as in PCa progression to a castrate resistant state. A recent study showed that after surgical castration of mice, the prostates from TNF−/− mice regressed significantly more slowly than those from wild-type mice, and that regression could be restored following administration of soluble TNF [22]. The slower rate of castration-induced prostate regression was also observed in TNFRI−/− mice, suggesting that TNF death signalling is required for normal prostate regression [22]. "
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