scholarly journals Differential Actions of Estrogen Receptor α and β via Nongenomic Signaling in Human Prostate Stem and Progenitor Cells

Endocrinology ◽  
2019 ◽  
Vol 160 (11) ◽  
pp. 2692-2708 ◽  
Author(s):  
Shyama Majumdar ◽  
Jaqueline C Rinaldi ◽  
Neha R Malhotra ◽  
Lishi Xie ◽  
Dan-Ping Hu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Estrogen Receptor ◽  
Progenitor Cells ◽  
Mapk Signaling ◽  
Human Prostate ◽  
Estrogen Signaling ◽  
Stem Cell Population ◽  
Normal Prostate ◽  
Phosphorylated Akt ◽  
Stem And Progenitor Cells

Abstract Human prostate stem and progenitor cells express estrogen receptor (ER)α and ERβ and exhibit proliferative responses to estrogens. In this study, membrane-initiated estrogen signaling was interrogated in human prostate stem/progenitor cells enriched from primary epithelial cultures and stem-like cell lines from benign and cancerous prostates. Subcellular fractionation and proximity ligation assays localized ERα and ERβ to the cell membrane with caveolin-1 interactions. Exposure to 17β-estradiol (E2) for 15 to 60 minutes led to sequential phosphorylation of signaling molecules in MAPK and AKT pathways, IGF1 receptor, epidermal growth factor receptor, and ERα, thus documenting an intact membrane signalosome that activates diverse downstream cascades. Treatment with an E2–dendrimer conjugate or ICI 182,870 validated E2-mediated actions through membrane ERs. Overexpression and knockdown of ERα or ERβ in stem/progenitor cells identified pathway selectivity; ERα preferentially activated AKT, whereas ERβ selectively activated MAPK cascades. Furthermore, prostate cancer stem-like cells expressed only ERβ, and brief E2 exposure activated MAPK but not AKT cascades. A gene subset selectively regulated by nongenomic E2 signaling was identified in normal prostate progenitor cells that includes BGN, FOSB, FOXQ1, and MAF. Membrane-initiated E2 signaling rapidly modified histone methyltransferases, with MLL1 cleavage observed downstream of phosphorylated AKT and EZH2 phosphorylation downstream of MAPK signaling, which may jointly modify histones to permit rapid gene transcription. Taken together, the present findings document ERα and ERβ membrane-initiated signaling in normal and cancerous human prostate stem/progenitor cells with differential engagement of downstream effectors. These signaling pathways influence normal prostate stem/progenitor cell homeostasis and provide novel therapeutic sites to target the elusive prostate cancer stem cell population.

scholarly journals Estrogen-Initiated Transformation of Prostate Epithelium Derived from Normal Human Prostate Stem-Progenitor Cells

Endocrinology ◽  
2011 ◽  
Vol 152 (6) ◽  
pp. 2150-2163 ◽  
Author(s):  
Wen-Yang Hu ◽  
Guang-Bin Shi ◽  
Hung-Ming Lam ◽  
Dan-Ping Hu ◽  
Shuk-Mei Ho ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Estrogen Receptor ◽  
Progenitor Cells ◽  
Progenitor Cell ◽  
Urogenital Sinus ◽  
Human Prostate ◽  
Normal Prostate ◽  
Normal Human ◽  
Prostate Epithelium ◽  
Estradiol 17Β

The present study sought to determine whether estrogens with testosterone support are sufficient to transform the normal human prostate epithelium and promote progression to invasive adenocarcinoma using a novel chimeric prostate model. Adult prostate stem/early progenitor cells were isolated from normal human prostates through prostasphere formation in three-dimensional culture. The stem/early progenitor cell status and clonality of prostasphere cells was confirmed by immunocytochemistry and Hoechst staining. Normal prostate progenitor cells were found to express estrogen receptor α, estrogen receptor β, and G protein-coupled receptor 30 mRNA and protein and were responsive to 1 nm estradiol-17β with increased numbers and prostasphere size, implicating them as direct estrogen targets. Recombinants of human prostate progenitor cells with rat urogenital sinus mesenchyme formed chimeric prostate tissue in vivo under the renal capsule of nude mice. Cytodifferentiation of human prostate progenitor cells in chimeric tissues was confirmed by immunohistochemistry using epithelial cell markers (p63, cytokeratin 8/18, and androgen receptor), whereas human origin and functional differentiation were confirmed by expression of human nuclear antigen and prostate-specific antigen, respectively. Once mature tissues formed, the hosts were exposed to elevated testosterone and estradiol-17β for 1–4 months, and prostate pathology was longitudinally monitored. Induction of prostate cancer in the human stem/progenitor cell-generated prostatic tissue was observed over time, progressing from normal histology to epithelial hyperplasia, prostate intraepithelial neoplasia, and prostate cancer with local renal invasion. These findings provide the first direct evidence that human prostate progenitor cells are estrogen targets and that estradiol in an androgen-supported milieu is a carcinogen for human prostate epithelium.

Allyl Isothiocyanate Induces Autophagy through the Up-Regulation of Beclin-1 in Human Prostate Cancer Cells

2018 ◽  
Vol 46 (07) ◽  
pp. 1625-1643 ◽  
Author(s):  
Hung-En Chen ◽  
Ji-Fan Lin ◽  
Te-Fu Tsai ◽  
Yi-Chia Lin ◽  
Kuang-Yu Chou ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Allyl Isothiocyanate ◽  
Beclin 1 ◽  
Human Prostate ◽  
Human Prostate Cancer ◽  
Prostate Cancer Cells ◽  
Normal Prostate ◽  
Autophagy Induction ◽  
Pc3 Cells

Allyl isothiocyanate (AITC), one of the most widely studied phytochemicals, inhibits the survival of human prostate cancer cells while minimally affecting normal prostate epithelial cells. Our study demonstrates the mechanism of AITC-induced cell death in prostate cancer cells. AITC induces autophagy in RV1 and PC3 cells, judging from the increased level of LC3-II protein in a dose- and time-dependent manner, but not in the normal prostate epithelial cell (PrEC). Inhibition of autophagy in AITC-treated cells decreased cell viability and enhanced apoptosis, suggesting that the autophagy played a protective role. There are several pathways activated in ATIC-treated cells. We detected the phosphorylation forms of mTOR, ERK, AMPK, JNK and p38, and ERK AMPK and JNK activation were also detected. However, inhibition of AITC-activated ERK, AMPK and JNK by pre-treatment of specific inhibitors did not alter autophagy induction. Finally, increased beclin-1 expression was detected in AITC-treated cells, and inhibition of AITC-induced beclin-1 attanuated autophagy induction, indicating that AITC-induced autophagy occurs through upregulating beclin-1. Overall, our data show for the first time that AITC induces protective autophagy in Rv1 and PC3 cells through upregulation of beclin-1. Our results could potentially contribute to a therapeutic application of AITC in prostate cancer patients.

scholarly journals Neurotensin Receptor-1 Expression in Human Prostate Cancer: A Pilot Study on Primary Tumors and Lymph Node Metastases

2019 ◽  
Vol 20 (7) ◽  
pp. 1721 ◽  
Author(s):  
Clément Morgat ◽  
Adrien Chastel ◽  
Vincent Molinie ◽  
Romain Schollhammer ◽  
Gaétan Macgrogan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Lymph Nodes ◽  
Distant Metastases ◽  
Human Prostate ◽  
Normal Prostate ◽  
Tissue Samples ◽  
Primary Tumors ◽  
Metastatic Lymph Nodes ◽  
Metastatic Lymph ◽  
Prostate Cancers

Neurotensin and its high-affinity receptor, NTR1, are involved in the growth of various tumors. Few data are available regarding NTR1 expression in normal and tumoral human prostate tissue samples. NTR1 expression was assessed using immunohistochemistry in 12 normal prostate tissues, 11 benign prostatic hyperplasia (BPH), 44 prostate cancers, and 15 related metastatic lymph nodes (one per patient, when available). NTR1-staining was negative in normal prostate and BPH samples. NTR1 was overexpressed in four out of 44 (9.1%) primary tumors. There was no clear association between NTR1 overexpression and age, PSA-values, Gleason score, pT-status, nodal-status, or margin. NTR1 was expressed at a high level of five out of 15 (33.3%) metastatic lymph nodes. NTR1 overexpression was thus more frequent in metastatic lymph nodes than in primary tumors (p = 0.038). In this limited series of samples, NTR1 overexpression was observed in few primary prostate cancers. Upregulation was more frequent in related lymph nodes. The presence of this target in metastatic lymph nodes may open new perspectives for imaging and radionuclide therapy of prostate cancer. Factors driving NTR1 expression in primary prostate cancer and in nodal and distant metastases still need to be characterized.

PrLZ Is Expressed in Normal Prostate Development and in Human Prostate Cancer Progression

2007 ◽  
Vol 13 (20) ◽  
pp. 6040-6048 ◽  
Author(s):  
Ruoxiang Wang ◽  
Jianchun Xu ◽  
Nicola Mabjeesh ◽  
Guodong Zhu ◽  
Jianguang Zhou ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Human Prostate ◽  
Human Prostate Cancer ◽  
Prostate Cancer Progression ◽  
Normal Prostate ◽  
Prostate Development

A new mechanism of estrogen action in prostate cancer: Inhibition of tissue androgen production and prostate cancer growth by Estradiol in androgen independent prostate cancer xenografts

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15509-15509
Author(s):  
B. Montgomery ◽  
P. Nelson ◽  
D. L. Hess ◽  
R. Vessella ◽  
E. Corey
Keyword(s):  
Prostate Cancer ◽  
Estrogen Receptor ◽  
Tumor Growth ◽  
Receptor Antagonist ◽  
Human Prostate ◽  
Human Prostate Cancer ◽  
Ici 182,780 ◽  
Estrogen Receptor Antagonist ◽  
Serum Androgens ◽  
Androgen Independent

15509 Background: Estrogens are effective agents in treating prostate cancer in patients in which serum androgens are already at ‘castrate‘ or anorchid levels. The mechanisms whereby estrogens inhibit ‘androgen-independent‘ prostate cancer are unclear. Methods: The androgen-independent human prostate cancer xenograft LuCaP 35V was implanted into orchiectomized male SCID mice and established tumors were treated with placebo pellets, 17β-estradiol (E2) slow-release pellets or E2 with the estrogen receptor antagonist ICI 182,780 as previously described (Clin Cancer Res 8:1003). Effects of E2 on tumor growth and tissue testosterone (T) and dihydrotestosterone (DHT) levels were evaluated by radioimmunoassay. Results: E2 significantly inhibited growth of androgen-independent LuCaP35V ( ∼35% inhibition at 4 weeks, p=0.0047, and increased survival of tumor bearing animals, (p trend =0.03) . The estrogen receptor antagonist ICI 182,780 did not block E2 inhibition of tumor growth, suggesting a receptor independent mechanism of tumor suppression. We then examined the effect of E2 on tissue T and DHT. E2 suppressed levels of tumor T and DHT in treated tumors. Tissue androgens in placebo treated LuCaP35V xenografts were; T=1.21 (± 0.18) pg/mg and DHT=3.54 (±1.07) pg/mg, and in E2-treated LuCaP35V T=0.23 (±0.09) pg/mg and DHT =0.44 (±0.14) pg/mg, (p<0.001). Levels of T and DHT in control liver tissue from both placebo and E2-treated animals were equivalent, at less than 0.2 pg/mg. Conclusions: We have shown that E2 inhibits growth of the androgen- independent human prostate cancer xenograft LuCaP35V, and that this inhibition is estrogen receptor independent. E2 significantly suppressed tumor tissue T and DHT suggesting a new mechanism of E2 mediated growth inhibition of androgen independent prostate cancer, potentially through inhibition of tumoral steroidogenesis. This model of ‘intracrine‘ tumor androgen production can be used to evaluate other inhibitors of tissue steroidogenesis. No significant financial relationships to disclose.

Targeting prostate cancer progenitor cells with telomerase interference: A novel therapeutic strategy

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22029-e22029
Author(s):  
A. Goldkorn ◽  
T. Xu
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Progenitor Cells ◽  
Cancer Progression ◽  
Cell Activation ◽  
Telomerase Activity ◽  
Human Prostate ◽  
Telomerase Rna ◽  
Prostate Tumors

e22029 Background: We investigated whether telomerase, which is critical for benign stem cell activation, also plays a role in prostate cancer progenitor cells (PCPCs), which are thought to mediate therapy resistance and cancer progression, and we tested whether telomerase interference can effectively inhibit PCPC proliferation. Methods: A putative PCPC population was isolated from human prostatectomy specimens via collagen attachment and FACS selection for integrin α2β1 and CD44. PCPCs were characterized for gene expression (RT-PCR), clonogenicity (colony formation), invasiveness (matrigel chamber), and telomerase activity (qPCR-TRAP). PCPC telomerase interference was accomplished by lentiviral expression of 2 constructs: telomerase RNA with an altered template region (MT-Ter) and siRNA targeting wild-type telomerase RNA (anti-Ter siRNA). The effects of these constructs were assessed by measuring PCPC viability (MTS) and apoptosis (TUNEL assay). Results: An integrin α2β1+CD44+ putative PCPC population was isolated from 6 human prostate tumors. This population expressed high levels of “progenitor phenotype” genes (ABCG2, β-catenin, NANOG, Oct3/4) and low levels of “differentiated phenotype” genes (AR and PSA). PCPCs yielded >50 colonies per 1000 cells seeded on collagen after 3 weeks vs. none from FACS- cells, and matrigel chamber assay showed 10% of the PCPC population invading over 24 hours vs. none of the FACS- population. Most importantly, PCPCs possessed at least 20- fold greater telomerase activity than FACS- cells, and induction of telomerase interference in PCPCs via MT-hTer and anti- hTer siRNA expression elicited a brisk apoptotic response (TUNEL) by day 3 in >90% of cells, with concomitant near-complete growth inhibition (MTS). Conclusions: We have shown that human prostate tumors contain a subpopulation of prostate cancer progenitor cells (PCPCs) marked by an undifferentiated gene expression profile, vigorous clonogenicity and invasiveness, and high levels of telomerase activity that can be successfully exploited to neutralize these cells. Ongoing studies are investigating the in vivo effects of telomerase interference on PCPC tumorigenicity in mouse models. No significant financial relationships to disclose.

scholarly journals Targeting of αv-Integrins in Stem/Progenitor Cells and Supportive Microenvironment Impairs Bone Metastasis in Human Prostate Cancer

Neoplasia ◽  
2011 ◽  
Vol 13 (6) ◽  
pp. 516-IN9 ◽  
Author(s):  
Geertje van der Horst ◽  
Christel van den Hoogen ◽  
Jeroen T. Buijs ◽  
Henry Cheung ◽  
Henny Bloys ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Progenitor Cells ◽  
Human Prostate ◽  
Human Prostate Cancer

scholarly journals The Endocrine-Gland-Derived Vascular Endothelial Growth Factor (EG-VEGF)/Prokineticin 1 and 2 and Receptor Expression in Human Prostate: Up-Regulation of EG-VEGF/Prokineticin 1 with Malignancy

Endocrinology ◽  
2006 ◽  
Vol 147 (9) ◽  
pp. 4245-4251 ◽  
Author(s):  
Daniela Pasquali ◽  
Valentina Rossi ◽  
Stefania Staibano ◽  
Gaetano De Rosa ◽  
Paolo Chieffi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Epithelial Cell ◽  
Cell Lines ◽  
Outcome Evaluation ◽  
Human Prostate ◽  
Endocrine Gland ◽  
Vascular Endothelial ◽  
Rt Pcr ◽  
Normal Prostate ◽  
Malignant Prostate

A new family of angiogenic factors named endocrine-gland-derived vascular endothelial growth factors (EG-VEGF)/prokineticins (PK) have been recently described as predominantly expressed in steroidogenic tissues. Whether the normal and malignant epithelial prostate cells and tissues express EG-VEGF/PK1 and PK2 and their receptors is still unknown. We studied the expression of EG-VEGF/PK1 and PK2 and their receptors (PK-R1 and PK-R2) in human prostate and their involvement in cancer. Using immunohistochemistry, Western blot, and RT-PCR, we determined the expression of EG-VEGF/PK1 in normal prostate (NP) and malignant prostate tissues (PCa), in epithelial cell primary cultures from normal prostate (NPEC) and malignant prostate (CPEC) and in a panel of prostate cell lines. In NPEC, CPEC, and in EPN, a nontransformed human prostate epithelial cell line, EG-VEGF/PK1, PK2, PK-R1, and PK-R2 mRNA levels were evaluated by quantitative RT-PCR. EG-VEGF/PK1 transcript was found in PCa, in CPEC, in EPN, and in LNCaP, whereas it was detected at low level in NP and in NPEC. EG-VEGF/PK1 was absent in androgen-independent PC3 and DU-145 cell lines. Immunochemistry confirmed that EG-VEGF/PK1 protein expression was restricted to hyperplastic and malignant prostate tissues, localized in the glandular epithelial cells, and progressively increased with the prostate cancer Gleason score advancement. EG-VEGF/PK1 and PK2 were weakly expressed in NPEC and EPN. On the other hand, their transcripts were highly detected in CPEC. PK-R1 and PK-R2 were found in NPEC, EPN, and CPEC. Interestingly, CPEC showed a significantly (P &lt; 0.05) higher expression of EG-VEGF/PK1, PK2, PK-R1, and PK-R2 compared with NPEC and EPN. We demonstrated that PKs and their receptors are expressed in human prostate and that their levels increased with prostate malignancy. It may imply that EG-VEGF/PK1 could be involved in prostate carcinogenesis, probably regulating angiogenesis. Thus, the level of EG-VEGF/PK1 could be useful for prostate cancer outcome evaluation and as a target for prostate cancer treatment in the future.

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