Transcription Factors Involved in Prostate Gland Adaptation to Androgen Deprivation

Abstract

Androgens regulate prostate physiology, and exert their effects through the androgen receptor. We hypothesized that androgen deprivation needs additional transcription factors to orchestrate the changes taking place in the gland after castration and for the adaptation of the epithelial cells to the androgen-deprived environment, ultimately contributing to the origin of castration-resistant prostate cancer. This study was undertaken to identify transcription factors that regulate gene expression after androgen deprivation by castration (Cas). For the sake of comparison, we extended the analysis to the effects of administration of a high dose of 17β-estradiol (E2) and a combination of both (Cas+E2). We approached this by (i) identifying gene expression profiles and enrichment terms, and by searching for transcription factors in the derived regulatory pathways; and (ii) by determining the density of putative transcription factor binding sites in the proximal promoter of the 10 most up- or down-regulated genes in each experimental group in comparison to the controls Gapdh and Tbp7. Filtering and validation confirmed the expression and localized EVI1 (Mecom), NFY, ELK1, GATA2, MYBL1, MYBL2, and NFkB family members (NFkB1, NFkB2, REL, RELA and RELB) in the epithelial and/or stromal cells. These transcription factors represent major regulators of epithelial cell survival and immaturity as well as an adaptation of the gland as an immune barrier in the absence of functional stimulation by androgens. Elk1 was expressed in smooth muscle cells and was up-regulated after day 4. Evi1 and Nfy genes are expressed in both epithelium and stroma, but were apparently not affected by androgen deprivation.

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

“…These diverse functions depend on poorly understood, complex gene expression networks and cell‐cell interactions. Accordingly, we have found that some genes escape the simplistic on‐or‐off expression pattern of androgen‐regulation via the androgen receptor (Rosa‐Ribeiro & Nishan et al, ).…”

Desquamation takes center stage at the origin of proliferative inflammatory atrophy, epithelial–mesenchymal transition, and stromal growth in benign prostate hyperplasia

“…The idea that the NFκB pathway might be implicated in the post‐castration behavior of the epithelium and contributes to desquamation is consistent with the modulation of NFκB family members after androgen deprivation (Rosa‐Ribeiro et al, ), but remains to be proven.…”

Redox-active and Redox-silent Compounds: Synergistic Therapeutics in Cancer

“…No TUNEL positivity was found in sections of the VK3/AAtreated tumours, suggesting that the reduction in tumour size induced by VK3/AA was due to tumour growth inhibition rather than induction of cell death. This was corroborated by the fact that at prolonged time of exposure to the drugs (days [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49], the tumours re-started to grow. Treatment with -TOS/VK3/AA significantly inhibited tumour growth (days 43-49, p = 0.04), inducing wide areas of cell death associated with AIF nuclear translocation, as compared to the control animals and those treated with the individual drugs.…”

“…Cells activate pathways in response to oxidative stress that promotes cell survival and adaptation [42,43]. The mechanism of cancer cell redox adaptation may involve multiple pathways to activate redox-sensitive transcription factors such as NF-B or the nuclear factor erythroid 2-related factor 2 (Nrf-2) [44,45] that can lead to increased expression of antioxidants such as SOD, CAT, and thioredoxin, and the GSH system. Under normal conditions, Nrf2 is targeted for proteasomal degradation by Kelch-like ECH-associated inhibitor protein-1 (Keap1).…”