Gonadotropin releasing hormone analogs induce apoptosis by extrinsic pathway involving p53 phosphorylation in primary cell cultures of human prostatic adenocarcinomas

Clementi, Marisa; Sánchez, Catherine; Benitez, Dixan A.; Contreras, Héctor R.; Huidobro, Christian; Cabezas, J.; Acevedo, Cristián; Castellón, Enrique A.

doi:10.1002/pros.20954

Cited by 20 publications

(17 citation statements)

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“…In our laboratory we developed cell culture systems from PCa explants to study several aspects of this disease, such as hormone sensitivity, drug resistance and the eff ect of various compounds with therapeutic potential Castellón et al 2006;Clementi et al 2009;Mendoza et al 2009;Sánchez et al 2005). The aim of this work was to isolate and characterize CSCs from our tumor explant-derived cultures in order to determine specific molecular stem signatures and to evaluate these markers in relation to Gleason grades and metastasis.…”

Section: Introductionmentioning

confidence: 99%

Molecular signature of cancer stem cells isolated from prostate carcinoma and expression of stem markers in different Gleason grades and metastasis

et al. 2012

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Prostate cancer (PCa) is the most frequently diagnosed malignancy in men worldwide. Chemotherapy response is very poor and resistance to hormone-based treatments is frequent in advances stages. Recently, tumor-initiating cells or cancer stem cells (CSCs) have been identifi ed in several cancers, including PCa. These cells are thought to be responsible for therapy resistance, relapse and metastasis. In the present work, enriched populations of CSCs were obtained using a mixed procedure that included diff erential clone-forming ability, sphere growing induction (prostatospheres) and magnetic-associated cell sorting (MACS). Also, stem marker expression was determined in PCa biopsies of diff erent histological grades and metastasis samples. The signature for stem markers of the isolated CSCs was CD133+/CD44+/ABCG2+/ CD24-. Expression of stem markers (CD133, CD44, and ABCG2) was higher in medium Gleason biopsies than in lower and higher grades, and lymph-node and bone metastasis samples. These results suggest that the CSCs in PCa reach an important number in medium Gleason grades, when the tumor is still confi ned into the gland. At this stage, the surgical treatment is usually with curative intention. However, an important percentage of patients relapse after treatment. Number and signature of CSCs may be a prognosis factor for PCa recurrence.

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Section: Introductionmentioning

confidence: 99%

Molecular signature of cancer stem cells isolated from prostate carcinoma and expression of stem markers in different Gleason grades and metastasis

et al. 2012

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“…Prolonged activation of Erk1/2 by GnRH favors cell death over proliferation and differentiation (Naor et al, ; Kraus et al, ; Naor, ); indeed, active Erk1/2 phosphorylates p53 at various sites, thereby directly regulating p53 action (Sablina et al, ; Shih et al, ; Lai et al, ; Choi et al, ). One particularly relevant modification is Erk1/2‐dependent phosphorylation of p53 at Ser15 (Li et al, ; Feng et al, ), a modification that is crucial for regulating p53‐mediated apoptosis and cell cycle control in malignant cells responding to GnRH and GnRH‐A (Imamura et al, ; Kraus et al, ; Shih et al, ; Kraus et al, ; Clementi et al, ; Moretti et al, ). In the canine testes, Erk1/2 was activated (phosphorylated) on the day of implant removal following 5 months of GnRH‐A treatment (Week 0); this elevated activity gradually tapered to levels of samples from untreated control animals by 24 weeks after implant removal (Fig.…”

Section: Discussionmentioning

confidence: 99%

Signaling events associated with gonadotropin releasing hormone‐agonist‐induced hormonal castration and its reversal in canines

Bulldan¹,

Shihan²,

Goericke-Pesch

et al. 2016

Molecular Reproduction Devel

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A gonadotropin-releasing hormone agonist (GnRH-A) implant induces hormonal castration in dogs that is associated with reduced prostate and testes size. We address the molecular events associated with hormonal castration by examining GnRH-A effects on expression and phosphorylation of a number of key signaling proteins. Male beagles were treated for 5 months with a GnRH-A implant, and then surgically castrated at 0, 3, 6, 12, and, 24 weeks after implant removal; untreated animals served as controls. GnRH-A treatment led to activation of c-Raf, Erk1/2, and, p53 in the testes. Phosphorylation of p53 occurred at Ser15, consistent with activation of the c-Raf-Erk1/2-p53 signaling cascade that triggers growth arrest or apoptosis. GnRH-A also suppressed the anti-apoptotic protein Bcl-xL; reduced phosphorylation of the transcription factors CREB and ATF1; and down-regulated expression of StAR and P450scc, proteins involved in steroidogenesis. Although androgen receptor expression was little affected by GnRH-A treatment, levels of ZIP9, a membrane-bound Zn transporter that mediates non-classical signaling of testosterone, were abrogated. All of these effects were reversed within 24 weeks after implant removal. Thus, molecular signatures of implant-dependent hormonal castration include reversible cell cycle arrest and apoptosis, loss of steroidogenesis, and reduced transcriptional activity. Mol. Reprod. Dev. 83: 1092-1101, 2016. © 2016 Wiley Periodicals, Inc.

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“…Lowering of estradiol levels with consequent antiproliferative action on the stroma [16] 4. Proapoptotic effects on prostate cells [17,18] 5. Relaxation of the detrusor and prostatic smooth muscles [19,20] In conclusion, the clinical development of the GnRH antagonist for the treatment of LUTS in patients with BPH highlights the potential pitfalls of rushing into patient testing before obtaining a clear understanding of the mechanism of action and thereby establishing a proper dose-response relationship for optimized clinical use.…”

Section: Proposed Mechanisms Of Action Of the Gnrh Antagonist In Lutsmentioning

confidence: 99%

Gonadotropin-Releasing Hormone Antagonists: From Basic Science to the Clinic in Patients With Benign Prostatic Hyperplasia and Lower Urinary Tract Symptoms

Colli¹,

Tankó²

2010

UIJ

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Abbreviations and AcronymsBPH =benign prostatic hyperplasia GnRH = gonadotropin-releasing hormone IPSS = International Prostate Symptom Score LUTS = lower urinary tract symptoms Qmax = maximum urinary flow rate ABSTRACT Gonadotropin-releasing hormone (GnRH) antagonists represent a new pharmacological class with several potential clinical indications. Although some of these indications (eg, prostate cancer) are clearly established, others are still in an exploratory phase and await confirmatory clinical trials to prove their clinical value in the treatment of target patients. Lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) are still investigational indications for GnRH antagonists. Although there have been several successful and hencepromising proof-of-concept clinical trials, the conflicting confirmatory data on cetrorelix and lack of clarity on the putative mechanism of action leaves us with work to do before this indication can be declared established. In this short review article, we outline the rationale for the use of GnRH antagonists in LUTS associated with BPH, summarize briefly the available clinical data (phase II and III trials) with the different compounds, touch upon the proposed mechanisms of action, and try to set perspectives for this field of research.

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Gonadotropin releasing hormone analogs induce apoptosis by extrinsic pathway involving p53 phosphorylation in primary cell cultures of human prostatic adenocarcinomas

Cited by 20 publications

References 56 publications

Molecular signature of cancer stem cells isolated from prostate carcinoma and expression of stem markers in different Gleason grades and metastasis

Molecular signature of cancer stem cells isolated from prostate carcinoma and expression of stem markers in different Gleason grades and metastasis

Signaling events associated with gonadotropin releasing hormone‐agonist‐induced hormonal castration and its reversal in canines

Gonadotropin-Releasing Hormone Antagonists: From Basic Science to the Clinic in Patients With Benign Prostatic Hyperplasia and Lower Urinary Tract Symptoms

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