The Role of the Capase-8 Inhibitor FLIP in Androgen-Withdrawal Induced Death of Prostate Epithelium

2006 ◽  
Author(s):  
John Krolewski ◽  
Kent Nastiuk
Keyword(s):  
Androgen Withdrawal ◽  
Prostate Epithelium

scholarly journals TGF-β maintains dormancy of prostatic stem cells in the proximal region of ducts

2005 ◽  
Vol 170 (1) ◽  
pp. 81-90 ◽  
Author(s):  
Sarah N. Salm ◽  
Patricia E. Burger ◽  
Sandra Coetzee ◽  
Ken Goto ◽  
David Moscatelli ◽  
...  
Keyword(s):  
Stem Cells ◽  
Transforming Growth Factor ◽  
Distal Region ◽  
Proximal Region ◽  
Cell Compartment ◽  
Androgen Ablation ◽  
Androgen Withdrawal ◽  
Prostatic Diseases ◽  
Prostatic Ducts

We have previously shown that prostatic stem cells are located in the proximal region of mouse prostatic ducts. Here, we show that this region responds differently to transforming growth factor (TGF)-β than the distal ductal region and that under physiological conditions androgens and TGF-β are crucial overall regulators of prostatic tissue homeostasis. This conclusion is supported by the observations showing that high levels of TGF-β signaling are present in the quiescent proximal region of ducts in an androgen-replete animal and that cells in this region overexpress Bcl-2, which protects them from apoptosis. Moreover, androgen ablation reverses the proximal-distal TGF-β signaling gradient, leading to an increase in TGF-β signaling in the unprotected distal region (low Bcl-2 expression). This reversal of TGF-β–mediated signaling accompanies apoptosis of cells in the distal region and gland involution after androgen withdrawal. A physiological TGF-β signaling gradient (high proximally and low distally) and its functional correlates are restored after androgen replenishment. In addition to highlighting the regulatory role of androgens and TGF-β, these findings may have important implications for the deregulation of the stem cell compartment in the etiology of proliferative prostatic diseases.

scholarly journals Progression of prostate carcinoma is promoted by adipose stromal cell-secreted CXCL12 signaling in prostate epithelium

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Fei Su ◽  
Alexes C. Daquinag ◽  
Songyeon Ahn ◽  
Achinto Saha ◽  
Yulin Dai ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Prostate Carcinoma ◽  
Stromal Cells ◽  
Epithelial Mesenchymal Transition ◽  
Genetic Model ◽  
Clinical Sample ◽  
Cxcl12 Expression ◽  
Mesenchymal Transition ◽  
Prostate Epithelium

AbstractAggressiveness of carcinomas is linked with tumor recruitment of adipose stromal cells (ASC), which is increased in obesity. ASC promote cancer through molecular pathways not fully understood. Here, we demonstrate that epithelial–mesenchymal transition (EMT) in prostate tumors is promoted by obesity and suppressed upon pharmacological ASC depletion in HiMyc mice, a spontaneous genetic model of prostate cancer. CXCL12 expression in tumors was associated with ASC recruitment and localized to stromal cells expressing platelet-derived growth factor receptors Pdgfra and Pdgfrb. The role of this chemokine secreted by stromal cells in cancer progression was further investigated by using tissue-specific knockout models. ASC deletion of CXCL12 gene in the Pdgfr + lineages suppressed tumor growth and EMT, indicating stroma as the key source of CXCL12. Clinical sample analysis revealed that CXCL12 expression by peritumoral adipose stroma is increased in obesity, and that the correlating increase in Pdgfr/CXCL12 expression in the tumor is linked with decreased survival of patients with prostate carcinoma. Our study establishes ASC as the source of CXCL12 driving tumor aggressiveness and outlines an approach to treatment of carcinoma progression.

Incidence of abiraterone acetate withdrawal response measured by PSA declines.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 280-280
Author(s):  
Rajasree Pia Chowdry ◽  
Brian E. Lewis ◽  
Elisa M. Ledet ◽  
Jonathan L. Silberstein ◽  
A. Oliver Sartor
Keyword(s):  
Therapy Response ◽  
Abiraterone Acetate ◽  
Response Evaluation ◽  
Androgen Withdrawal ◽  
Psa Response ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant ◽  
Hormonal Therapies ◽  
Withdrawal Response

280 Background: The anti-androgen withdrawal effect is a well-described phenomenon occurring in patients with castrate resistant prostate cancer (CRPC) after discontinuing anti-androgen therapy. There is limited data on withdrawal responses after newer hormonal therapies such as Abiraterone Acetate (AA). Discontinuation of AA may lead to PSA declines but the frequency remains unclear. The goal of our study was to assess the incidence and duration of PSA decreases after stopping AA. Methods: We reviewed 51 patients with CRPC who had discontinued AA therapy at a single institution (6/2009-6/2014). PSA values were assessed before, during, and after stopping AA therapy. Response was defined as >50% PSA decline post-AA stoppage, with no additional therapy added. Results: From 51 patients treated with AA, only 22 (43%) were eligible for withdrawal response evaluation. A total of 29 patients (57%) were changed to alternate therapies too soon for withdrawal response evaluation. Of the 22 evaluable patients, AA withdrawal was seen in 2 patients (9%). The first patient had a 72% reduction in PSA upon discontinuation of AA, with PSA dropping from 330 (ng/mL) to 93 over 16 days. Previously administered dexamethasone was continued. He had been on AA therapy for 12 months. Time to next treatment was only 1 month so PFS was not ascertainable. The second patient had a 60% reduction in PSA after simultaneously discontinuing both AA and prednisone. His PSA declined from 25.1 to 9.9 over 2 months. He had received only 2 prior months of AA and prednisone and had a clear PSA rise during this therapy. PFS after AA and prednisone discontinuation was 3 months. Time to next treatment was 6 months. Neither patient who responded to AA withdrawal had a prior bicalutamide withdrawal response. Conclusions: PSA response to AA withdrawal is a known, but poorly understood phenomenon that occurs in a subset of patients. Larger studies with longer follow-up are needed to define the incidence of this observation. The potential role of glucocorticoids in this process needs additional elucidation.

scholarly journals CPT1A Supports Castration-Resistant Prostate Cancer in Androgen-Deprived Conditions

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1115 ◽  
Author(s):  
Joshi ◽  
Stoykova ◽  
Salzmann-Sullivan ◽  
Dzieciatkowska ◽  
Liebman ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Histone Acetylation ◽  
Specific Inhibitor ◽  
Dependent Manner ◽  
Castration Resistant Prostate Cancer ◽  
Lipid Catabolism ◽  
Castration Resistant ◽  
Common Cancer ◽  
Androgen Withdrawal

Prostate cancer (PCa) is the most common cancer in men, and the global burden of the disease is rising. The majority of PCa deaths are due to metastasis that are highly resistant to current hormonal treatments; this state is called castration-resistant prostate cancer (CRPC). In this study, we focused on the role of the lipid catabolism enzyme CPT1A in supporting CRPC growth in an androgen-dependent manner. We found that androgen withdrawal promoted the growth of CPT1A over-expressing (OE) tumors while it decreased the growth of CPT1A under-expressing (KD) tumors, increasing their sensitivity to enzalutamide. Mechanistically, we found that CPT1A-OE cells burned more lipid and showed increased histone acetylation changes that were partially reversed with a p300 specific inhibitor. Conversely, CPT1A-KD cells showed less histone acetylation when grown in androgen-deprived conditions. Our results suggest that CPT1A supports CRPC by supplying acetyl groups for histone acetylation, promoting growth and antiandrogen resistance.

scholarly journals Lxrα Regulates the Androgen Response in Prostate Epithelium

Endocrinology ◽  
2012 ◽  
Vol 153 (7) ◽  
pp. 3211-3223 ◽  
Author(s):  
Emilie Viennois ◽  
Teresa Esposito ◽  
Julie Dufour ◽  
Aurélien Pommier ◽  
Stephane Fabre ◽  
...  
Keyword(s):  
Benign Prostatic Hyperplasia ◽  
Molecular Mechanisms ◽  
Fold Increase ◽  
Prostatic Hyperplasia ◽  
Vesicular Trafficking ◽  
Ventral Prostate ◽  
Mouse Prostate ◽  
Prostate Epithelium ◽  
Prostatic Ducts

Benign prostatic hyperplasia is a nonmalignant enlargement of the prostate that commonly occurs in older men. We show that liver X receptor (Lxr)-α knockout mice (lxrα−/−) develop ventral prostate hypertrophy, correlating with an overaccumulation of secreted proteins in prostatic ducts and an alteration of vesicular trafficking in epithelial cells. In the fluid of the lxrα−/− prostates, spermine binding protein is highly accumulated and shows a 3000-fold increase of its mRNA. This overexpression is mediated by androgen hypersensitivity in lxrα−/− mice, restricted to the ventral prostate. Generation of chimeric recombinant prostates demonstrates that Lxrα is involved in the establishment of the epithelial-mesenchymal interactions in the mouse prostate. Altogether these results point out the crucial role of Lxrα in the homeostasis of the ventral prostate and suggest lxrα−/− mice may be a good model to investigate the molecular mechanisms of benign prostatic hyperplasia.

Sign in / Sign up

Export Citation Format

Share Document