Stromally Expressed c-Jun Regulates Proliferation of Prostate Epithelial Cells

Abstract

Stromal-epithelial interactions play a critical role inBenign prostatic hyperplasia (BPH) is the most common age-related proliferative abnormality of the human prostate affecting elderly men throughout the world. Half of all men have BPH identifiable histologically by age 60, and by age 85 the prevalence is ϳ90%. 1 The excessive cell proliferation associated with BPH causes benign prostatic enlargement, bladder outlet obstruction, and lower urinary tract symptoms, which afflict the patients. 2 BPH is a histological diagnosis associated with both epithelial and stromal (fibroblasts and smooth muscle cells of prostate) hyperplasia. 3 Cellular alterations that include changes in proliferation, differentiation, apoptosis, and senescence in the epithelium and stroma are implicated in the pathogenesis of BPH. Medical treatments available to patients with BPH target both prostatic stromal and epithelial cells.Watchful waiting, pharmacological therapy, and surgery are three treatment modalities for BPH patients. Medical therapy is a long-term commitment for the patient. Surveys show that a large number of patients discontinue therapy, often because they perceive lack of efficacy and/or experience side effects. 4,5 We can accordingly improve our treatment of BPH by better targeted medical therapy to decrease the number of invasive therapies for this benign disease. Better alternative and improved therapies can be achieved by studying the normal and abnormal reciprocal cross talk between prostatic stromal and epithelial cells.Stromal-epithelial interactions play a critical role in the development and growth of the prostate gland and BPH. Cunha and colleagues 6 -8 have demonstrated that the stromal embryonic tissue is responsible for instructing the proper development of prostate epithelial cells. Tissue recombinants between embryonic urogenital sinus mesenchyme and adult prostatic tissue have demonstrated that the fetal mesenchyme can drive differentiation and growth of adult prostatic epithelial cells. 9 It has been proposed that BPH may be caused by reactivation of dormant embryonic growth in the adult stroma. 10 The proliferation of the stromal elements can stimulate the ingrowth of epithelial cells to produce a benign hyperplastic growth that is recognized

Local insulin-like growth factor-I of ventral prostate was upregulated during long-term castration and may function through the autocrine system

“…These results suggested that the site of IGF-I may vary at different stage after castration; other studies also proved that the IGF-I synthesis may be different in certain circumstance and vary in different species. [15][16][17] In conclusion, we report here that although IGF-I of local VP decreases sharply in short-stage castration, its levels increase gradually and remain at high levels at least until 24 weeks after castration. IGF-I may act as a replacement for androgen by autocrine methods in the case of long-term castration.…”

“…3,14 IGF-I, one of the epithelial-stromal interaction factors, promotes prostate epithelial proliferation and anti-apoptosis through paracrine or autocrine way and is principally synthesized in prostate stroma or in the epithelium, or in both of these tissue compartments. [15][16][17] Previous study reported that IGF-I is synthesized mainly by stroma in short-stage castration, and may have a role through paracrine or autocrine way; 11 however, the sites of IGF-1 production in long-term castration (up to 24 weeks) is still unknown.…”

Intermediate-Conductance Ca2+-Activated K+ Channel, KCa3.1, as a Novel Therapeutic Target for Benign Prostatic Hyperplasia

“…5B). Li et al (2007) have shown that c-Jun is abundantly expressed in the prostatic stroma but not in the epithelium of human BPH samples, and c-Jun is expressed at high levels in BPH nodules enriched with stroma. In the present study, positive correlations between K Ca 3.1 and c-Jun were significant in both implanted UGS and prostate needle biopsies from BPH patients (Figs.…”

Phosphorylation-induced Conformational Ensemble Switching in an Intrinsically Disordered Cancer/Testis Antigen

“…The amplifying effect on c-Jun transactivation suggests that PAGE4 may modulate the activity of AP-1. Notably, c-Jun is also up-regulated in the developing (20) and diseased prostate (21)(22)(23)(24)(25)(26), whereas the AP-1 complex is up-regulated in symptomatic benign prostatic hyperplasia (27) as well as in prostate cancer (28). These patterns are coincident with PAGE4 expression (13) and underscore the importance of the PAGE4/c-Jun interactions in prostatic development and disease.…”