Abstract As a key glycolytic enzyme, enolase 1 (ENO1) is critical for cellular energy metabolism. Recent studies have revealed its important role in growth and metastasis of lung, head and neck, and breast cancer. However, the regulatory mechanisms of ENO1 expression and secretion remain unclear. We observed that conditioned medium from estradiol-stimulated prostate stromal cells significantly promoted the migration of prostate cancer (PCa) cells. Two-dimensional protein electrophoresis, mass spectrometry, and immunodepletion assays identified one of the major active factors in the conditioned medium as α-type enolase (α-enolase, or ENO1). Moreover, in prostate stromal cells, estradiol not only enhanced the stability of ENO1 at the protein level in an estrogen receptor-α-dependent manner but also promoted its secretion to the extracellular matrix. Furthermore, recombinant ENO1 bound to the surface of PCa cells and promoted cell migration via their plasminogen receptor activity in a paracrine manner. Immunohistochemistry suggested that stromal ENO1 levels increased in PCa compared with those in normal tissue.

10.1210/me.2012-1006

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1611 QUANTITATIVE MEASUREMENT OF THE ANDROGEN RECEPTOR IN PREPUCES OF BOYS WITH AND WITHOUT HYPOSPADIAS

The Journal of Urology (2012)

Renate Pichler Gabriel Djedovic Helmut Klocker Verena Hauser Georg Schäfer

You have accessJournal of UrologyPediatrics: Congenital Anomalies - Lower Urinary Tract & Genitalia II1 Apr 20121611 QUANTITATIVE MEASUREMENT OF THE ANDROGEN RECEPTOR IN PREPUCES OF BOYS WITH AND WITHOUT HYPOSPADIAS Renate Pichler, Gabriel Djedovic, Helmut Klocker, Verena Hauser, Georg Schäfer, Christian Radmayr, Wolfgang Horninger, and Josef Oswald Renate PichlerRenate Pichler Innsbruck, Austria More articles by this author , Gabriel DjedovicGabriel Djedovic Innsbruck, Austria More articles by this author , Helmut KlockerHelmut Klocker Innsbruck, Austria More articles by this author , Verena HauserVerena Hauser Innsbruck, Austria More articles by this author , Georg SchäferGeorg Schäfer Innsbruck, Austria More articles by this author , Christian RadmayrChristian Radmayr Innsbruck, Austria More articles by this author , Wolfgang HorningerWolfgang Horninger Innsbruck, Austria More articles by this author , and Josef OswaldJosef Oswald Innsbruck, Austria More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.1406AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The etiology of hypospadias is not yet understood. The aim of this study was to quantify and compare the androgen receptor (AR) mRNA and protein in prepuces of boys with and without hypospadias. METHODS 40 prepuce specimens of circumcised boys (20 with and 20 without hypospadias) were enrolled in this prospective study. Mean age was 61.8 (range 18 to 162) and 30.9 (range 13 to 156) months in children without and with hypospadias at time of surgery. Coronal, penile and sine hypospadias were seen in 9 (45%), 7 (35%) and 4 (20%) children respectively. Immediately after surgery tissue samples were divided, one part was fixed in formaldehyde and embedded in paraffin, the other one was snap frozen in liquid nitrogen at -80° C. Total RNA was isolated from frozen tissue and transcribed to cDNA. The amount of androgen receptor mRNA was measured by quantitative real time PCR. Western Blot and standardized, automated immunohistochemistry (Discovery XT, Ventana) were used to assess androgen receptor protein levels. RESULTS The androgen receptor mRNA expression was significantly elevated in the prepuces of boys with hypospadias compared to boys with phimosis (28.33±5.39 vs. 15.31±1.85, p<0.05). Furthermore, the amount of androgen receptor protein was higher in boys with, compared to boys without hypospadias (133.25±6.17 vs. 100±4.45, p<0.05). These results suggest that a decreased androgen receptor DNA binding and functional capability elicits a compensatory up-regulation of androgen receptor mRNA and protein. CONCLUSIONS Our results suggest that the different androgen receptor mRNA and protein expression levels indicate the extent of androgen receptor signaling defects in boys with hypospadias. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e652 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Renate Pichler Innsbruck, Austria More articles by this author Gabriel Djedovic Innsbruck, Austria More articles by this author Helmut Klocker Innsbruck, Austria More articles by this author Verena Hauser Innsbruck, Austria More articles by this author Georg Schäfer Innsbruck, Austria More articles by this author Christian Radmayr Innsbruck, Austria More articles by this author Wolfgang Horninger Innsbruck, Austria More articles by this author Josef Oswald Innsbruck, Austria More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

10.1016/j.juro.2012.02.1406

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The HeyL-Aromatase Axis Promotes Cancer Stem Cell Properties by Endogenous Estrogen-Induced Autophagy in Castration-Resistant Prostate Cancer

Frontiers in Oncology (2022)

Qimei Lin Jiasong Cao Xiaoling Du Kuo Yang Yongmei Shen

Treatment of patients with castration-resistant prostate cancer (CRPC) remains a major clinical challenge. We previously showed that estrogenic effects contribute to CRPC progression and are primarily caused by the increased endogenous estradiol produced via highly expressed aromatase. However, the mechanism of aromatase upregulation and its role in CRPC are poorly described. In this study, we report that HeyL is aberrantly upregulated in CRPC tissues, and its expression is positively correlated with aromatase levels. HeyL overexpression increased endogenous estradiol levels and estrogen receptor-α (ERα) transcriptional activity by upregulating CYP19A1 expression, which encodes aromatase, enhancing prostate cancer stem cell (PCSC) properties in PC3 cells. Mechanistically, HeyL bound to the CYP19A1 promoter and activated its transcription. HeyL overexpression significantly promoted bicalutamide resistance in LNCaP cells, which was reversed by the aromatase inhibitor letrozole. In PC3 cells, the HeyL-aromatase axis promoted the PCSC phenotype by upregulating autophagy-related genes, while the autophagy inhibitor chloroquine (CQ) suppressed the aromatase-induced PCSC phenotype. The activated HeyL-aromatase axis promoted PCSC autophagy via ERα-mediated estrogenic effects. Taken together, our results indicated that the HeyL-aromatase axis could increase endogenous estradiol levels and activate ERα to suppress PCSC apoptosis by promoting autophagy, which enhances the understanding of how endogenous estrogenic effects influence CRPC development.

10.3389/fonc.2021.787953

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Table S1 from The Glucocorticoid Receptor Is a Key Player for Prostate Cancer Cell Survival and a Target for Improved Antiandrogen Therapy

Martin Puhr Julia Hoefer Andrea Eigentler Christian Ploner Florian Handle

Table S1

Table (database)

10.1158/1078-0432.22465317.v1

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Figure S3 from The Glucocorticoid Receptor Is a Key Player for Prostate Cancer Cell Survival and a Target for Improved Antiandrogen Therapy

Martin Puhr Julia Hoefer Andrea Eigentler Christian Ploner Florian Handle

Analysis of 3D-spheroid growth after GR knockdown with 1µg/ml doxycycline for 8 d in PC3, DU145, CWR22Rv1, LAPC4, and DUCaP cells (data represent Box Whisker Plots with 10-90 percentile from 3 independent experiments; ***, p< 0.001).

DU145

10.1158/1078-0432.22465341.v1

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Figure S2 from The Glucocorticoid Receptor Is a Key Player for Prostate Cancer Cell Survival and a Target for Improved Antiandrogen Therapy

Martin Puhr Julia Hoefer Andrea Eigentler Christian Ploner Florian Handle

(A) GR knockdown confirmation by Western blot analysis using 2 specific doxycycline inducible shGR-RNA sequences (shGR-1 and shGR-2) after activation with 1 µg/ml doxycycline for 6 d in DUCaP.

10.1158/1078-0432.22465344.v1

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Inhibitory effects of the nucleoside analogue gemcitabine on prostatic carcinoma cells

The Prostate (1996)

Marcus V. Cronauer Helmut Klocker Heribert Talasz Françoise Geisen Alfred Hobisch

Gemcitabine (2≺,2≺difluoro-2≺deoxycytidine, dFdC) is a synthetic antimetabolite of the cellular pyrimidine nucleotide metabolism. In a first series of in vitro experiments, the drug showed a strong effect on the proliferation and colony formation of the human androgen-sensitive tumor cell line LNCaP and the androgen-insensitive cell lines PC-3 and DU-145. Maximal inhibition occurred at a dFdC concentration as low as 30 nM. In contrast to the cell lines which were derived from metastatic lesions of prostate cancer patients, no inhibitory effects were found in normal primary prostatic epithelial cells at concentrations up to 100 nM. The effect of gemcitabine was reversed by co-administration of 10–100 μM of its natural analogue deoxycytidine. In view of a future clinical application of this anti-tumor drug in advanced prostatic carcinoma, we have compared the effect of gemcitabine on prostatic tumor cells with that on bone marrow granulopoietic-macrophagic progenitor cells, because neutropenia is a common side effect of gemcitabine treatment. The time course of action on the two kinds of cells was markedly different. Colony formation of tumor cells was inhibited by two thirds at a gemcitabine concentration of about 3.5 nM. The same effect on granulopoietic-macrophagic progenitor cells required a concentration of 9 nM. Co-administration of deoxycytidine to gemcitabine-treated tumor cell cultures completely antagonized the effect of gemcitabine whereas addition of deoxycytidine after 48 hr of gemcitabine treatment could not prevent gemcitabine action on the tumor cells. In contrast, more than half of the granulopoietic-macrophagic progenitor cells could still be rescued by deoxycytidine administration after 48 hr. These findings and the marked difference in the susceptibility of neoplastic and normal prostatic cells suggest that gemcitabine is a promising substance which should be further evaluated as to its efficacy in the treatment of advanced prostatic carcinoma. © 1996 Wiley-Liss, Inc.

Nucleoside analogue

10.1002/(sici)1097-0045(199603)28:3<172::aid-pros4>3.3.co;2-9

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Novel mechanism of IGF-binding protein-3 action on prostate cancer cells: inhibition of proliferation, adhesion, and motility

Endocrine Related Cancer (2009)

Petra Massoner Daniela Colleselli Andrea Matscheski Haymo Pircher Stephan Geley

IGF-binding protein-3 (IGFBP-3) is a modulator of the IGF-signaling pathway and was described as an anti-cancer agent in prostate cancer. The molecular mechanisms underlying these effects remained, however, largely undefined. We analyzed the influence of recombinant IGFBP-3 on cell proliferation of PC3, Du145, and LNCaP prostate cancer cells. As expected, IGFBP-3 inhibited IGF-stimulated cell proliferation by blocking IGF-mediated proliferation signals, but we observed an IGF-independent inhibitory effect of IGFBP-3 on prostate cancer cell proliferation in long-term cultures. We further investigated the influence of IGFBP-3 on adhesion, motility, and invasion of prostate cancer cells using adhesion assays, live-cell imaging techniques, and matrigel invasion measurements. There was a clear inhibitory effect of IGFBP-3 on tumor cell adhesion to extracellular matrix components in the presence and absence of IGF, whereas cell-cell adhesion was not affected. The same inhibitory effect of IGFBP-3 was determined on cell motility when real-time cell movements were followed. In addition, IGFBP-3 was able to inhibit tumor cell invasion through matrigel. In summary, we show that IGFBP-3 inhibits proliferation, adhesion, migration, and invasion processes of prostate tumor cells. These newly described mechanisms of IGFBP-3 can be of importance for tumor progression and support a role of IGFBP-3 in therapeutic settings.

Mechanism of Action

10.1677/erc-08-0175

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