scholarly journals Androgen Deprivation Induces Reprogramming of Prostate Cancer Cells to Stem-Like Cells

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1441 ◽  
Author(s):  
Belén G. Sánchez ◽  
Alicia Bort ◽  
Diana Vara-Ciruelos ◽  
Inés Díaz-Laviada
Keyword(s):  
Prostate Cancer ◽  
Hypoxia Inducible Factor ◽  
Neuron Specific Enolase ◽  
Angiogenic Factor ◽  
Stem Cell Markers ◽  
Lncap Cells ◽  
Androgen Receptor Antagonist ◽  
Enhanced Expression ◽  
Androgen Depletion ◽  
E Cadherin

In the past few years, cell plasticity has emerged as a mode of targeted therapy evasion in prostate adenocarcinoma. When exposed to anticancer therapies, tumor cells may switch into a different histological subtype, such as the neuroendocrine phenotype which is associated with treatment failure and a poor prognosis. In this study, we demonstrated that long-term androgen signal depletion of prostate LNCaP cells induced a neuroendocrine phenotype followed by re-differentiation towards a “stem-like” state. LNCaP cells incubated for 30 days in charcoal-stripped medium or with the androgen receptor antagonist 2-hydroxyflutamide developed neuroendocrine morphology and increased the expression of the neuroendocrine markers βIII-tubulin and neuron specific enolase (NSE). When cells were incubated for 90 days in androgen-depleted medium, they grew as floating spheres and had enhanced expression of the stem cell markers CD133, ALDH1A1, and the transporter ABCB1A. Additionally, the pluripotent transcription factors Nanog and Oct4 and the angiogenic factor VEGF were up-regulated while the expression of E-cadherin was inhibited. Cell viability revealed that those cells were resistant to docetaxel and 2-hidroxyflutamide. Mechanistically, androgen depletion induced the decrease in AMP-activated kinase (AMPK) expression and activation and stabilization of the hypoxia-inducible factor HIF-1α. Overexpression of AMPK in the stem-like cells decreased the expression of stem markers as well as that of HIF-1α and VEGF while it restored the levels of E-cadherin and PGC-1α. Most importantly, docetaxel sensitivity was restored in stem-like AMPK-transfected cells. Our model provides a new regulatory mechanism of prostate cancer plasticity through AMPK that is worth exploring.

A Phase II Study of 5-AZA-2'Deoxycytidine (Decitabine) in Hormone Independent Metastatic (D2) Prostate Cancer

1998 ◽  
Vol 84 (1) ◽  
pp. 87-89 ◽  
Author(s):  
Alain Thibault ◽  
William D. Figg ◽  
Raymond C. Bergan ◽  
Richard M. Lush ◽  
Charles E. Myers ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
African American ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Angiogenic Factor ◽  
Clinical Activity ◽  
Expression Of Genes ◽  
Potential Biomarker ◽  
Enhanced Expression ◽  
Laboratory Models

Aims and Background Decitabine (5-aza-2′-deoxycytidine) is an S-phase-specific pyrimidine analog with hypomethylation properties. In laboratory models of prostate cancer (PC-3 and DU-145), decitabine induces cellular differentiation and enhanced expression of genes involved in tumor suppression, immunogenicity, and programmed cell death. Methods We conducted a phase II study of decitabine in 14 men with progressive, metastatic prostate cancer recurrent after total androgen blockade and flutamide withdrawal. Decitabine was administered at a dose of 75 mg/m2/dose IV as a 1 hour infusion every 8 hours for three doses. Cycles of therapy were repeated every 5 to 8 weeks to allow for resolution of toxicity. Results Two of 12 patients evaluable for response had stable disease with a time to progression of more than 10 weeks. This activity was seen in 2 of 3 African-American patients. Toxicity was similar to previously reported experience. No significant changes in urinary concentrations of the angiogenic factor bFGF, a potential biomarker of tumor activity, were identified over time in 7 unselected patients with progressive disease. Conclusions We conclude that decitabine is a well tolerated regimen with modest clinical activity against hormone-independent prostate cancer. Further investigations in patients of African-American origin may be warranted.

Hypoxia-inducible factor 1α: A screening tool for predicting development of castrate resistant prostate cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15117-e15117
Author(s):  
Weranja Kalana Bodhisiri Ranasinghe ◽  
Lin Xiao ◽  
Suzana Kovac ◽  
Mike Chang ◽  
Arthur Shulkes ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Screening Tool ◽  
Hypoxia Inducible Factor ◽  
Protein Translation ◽  
Lncap Cells ◽  
Free Survival ◽  
Castrate Resistant Prostate Cancer ◽  
Pc3 Cells ◽  
Castrate Resistant

e15117 Background: Currently there is no method to determine which patients starting androgen deprivation therapy (ADT) for prostate cancer (PC) will progress to castrate resistant prostate cancer (CRPC) while the reasons for early metastases and chemoresistance in CRPCs are unknown. We aimed to investigate the potential role of hypoxia inducible factor 1α (HIF1α), a key transcription factor in the cell mediated adaptive response to changes in tissue oxygenation, in predicting the development of CRPC. Methods: 100 prostate tumour samples were divided into Gleason ≤7 (38) and Gleason >7 (62) and stained for HIF1α using immunohistochemistry, blinded to the outcomes. The outcomes of CRPC, metastases and PC specific death were measured and correlated with HIF1α expression. In vitro, the effects of HIF1α on proliferation, survival and migration of PC cells were assessed by cell count and Boyden chamber assays. Results: HIF1α expression in PC was independent of Gleason grade and tumour stage. HIF1α was an independent risk factor for development of CRPC (Hazard Ratio (HR) 10.4), progression to metastases (HR 9.8) and PC specific death (HR 13.4) at median times of 23, 24 and 25 months respectively, from the start of ADT on a multivariate Cox regression analysis (all p<0.05) adjusted for Gleason score, PSA and age. CRPC free survival, metastases free survival and PC specific survival were all significantly decreased in patients with HIF1α on Kaplan Meier analyses. The presence of HIF1α was highly sensitive (all 100%) with excellent negative predictive values (all 100%) for all 3 outcomes, but had poor specificity. HIF1α over-expressing PC3 cells (CRPC) were compared with androgen sensitive LNCaP cells in vitro. PC3 cells were resistant to cytotoxic agents including H2O2 (oxidative stress) and 5-fluorouracil (chemotherapy agent) and had higher rates of migration compared to LNCaP cells. HIF1α knockdown in PC3 cells reversed these effects. Protein translation efficiency in PC3 cells was significantly higher than LNCaP cells. Conclusions: HIF1α is a good screening tool for CRPC. HIF1α expression is likely to contribute to metastases and chemoresistance of CRPCs and is likely upregulated at protein translation in PC cells.

Potential increase in androgen sensitivity following antisense oligonucleotide suppression of Bcl-2 in a prostate cancer model.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13532-e13532
Author(s):  
Patrick Guinan ◽  
Marvin Rubenstein ◽  
Courtney M.P. Hollowell
Keyword(s):  
Prostate Cancer ◽  
Creb Binding Protein ◽  
Lncap Cells ◽  
Altered Expression ◽  
Androgen Sensitivity ◽  
Enhanced Expression ◽  
Increased Sensitivity ◽  
Apoptosis Inhibitor

e13532 Background: Antisense oligonucleotides (oligos) have been employed against in vivo and in vitro prostate cancer models targeting growth stimulatory gene products. While most oligos have targeted growth factors or their receptors, others have been directed against inhibitors of apoptosis and mediators of androgen action. In LNCaP cells we evaluated a set of oligos which targeted and comparably suppressed the expression of the apoptosis inhibitor protein bcl-2. To evaluate the specificity of this type of gene therapy, targeted and non-targeted genes were evaluated for their expression. The purpose was to identify whether additional (non-targeted) genes altered their expression in a manner which could circumvent or compensate for the suppression of bcl-2, promoting growth through increased androgen sensitivity. Methods: LNCaP prostate cells were treated with mono- and bispecific oligos directed against bcl-2. Employing RT-PCR the expression of both targeted and non-targeted genes (androgen receptor [AR], coactivators p300 and creb binding protein [CREB]) was determined. Results: LNCaP cells adapted to the suppression of bcl-2 (an apoptosis inhibitor) with enhanced expression of both AR and p300. This suggests an increased sensitivity to androgens. Conclusions: In this model, oligo treatment directed against bcl-2, may be evaded through a compensatory increase in both AR and p300 expression. This promotion of tumor growth, and the altered expression of AR coactivators normally seen in advanced disease, suggests a tumor transition to a more aggressive phenotype following suppressive treatment directed against bcl-2.

scholarly journals Involvement of Cholesterol-Rich Lipid Rafts in Interleukin-6-Induced Neuroendocrine Differentiation of LNCaP Prostate Cancer Cells

Endocrinology ◽  
2004 ◽  
Vol 145 (2) ◽  
pp. 613-619 ◽  
Author(s):  
Jayoung Kim ◽  
Rosalyn M. Adam ◽  
Keith R. Solomon ◽  
Michael R. Freeman
Keyword(s):  
Prostate Cancer ◽  
Signal Transduction ◽  
Lipid Rafts ◽  
Lipid Raft ◽  
Neuron Specific Enolase ◽  
Membrane Microdomains ◽  
Membrane Rafts ◽  
Lncap Cells ◽  
Discontinuous Sucrose Gradient ◽  
Triton X

Abstract IL-6 is an inflammatory cytokine that has been linked to aggressive prostate cancer (PCa). Previous studies have demonstrated that IL-6 can enhance the differentiation of PCa cells toward a neuroendocrine (NE) phenotype, a possible indicator of hormone-refractory disease. In this report, we present evidence that the mechanism of IL-6-stimulated NE differentiation employs a detergent-resistant (lipid raft) membrane compartment for signal transduction in LNCaP PCa cells. Signal transducer and activator of transcription (STAT)3, a mediator of IL-6 signaling, was rapidly phosphorylated and translocated to the nucleus in LNCaP cells treated with IL-6. Both processes were inhibited by filipin, a cholesterol-binding compound that disrupts plasma membrane lipid rafts. Isolation of Triton X-100-insoluble raft fractions from LNCaP cells by discontinuous sucrose gradient centrifugation demonstrated that the 80-kDa IL-6 receptor localized almost exclusively to the raft compartment. Although STAT3 was located predominantly in the Triton X-100-soluble subcellular fraction in exponentially growing cells, abundant phosphorylated STAT3 was detected in the raft fraction after stimulation with IL-6. Increases in expression of the NE marker, neuron-specific enolase, and neuron-specific enolase promoter activity after IL-6 treatment were reduced after membrane rafts were disrupted by filipin treatment. LNCaP cells expressed the raft-resident proteins flotillin-2 and Giα2, but notably not caveolins, the predominant structural protein present in caveolar membrane rafts in many tissues and tumor cells. These results are the first to define a role for lipid raft membrane microdomains in signal transduction mechanisms capable of promoting the NE phenotype in PCa cells, and they demonstrate that the raft compartment is capable of mediating such signals in the absence of caveolins. Our results also suggest a mechanistic role for membrane cholesterol in cell signaling events relevant to PCa progression.

scholarly journals Tamarix Articulata Exhibits Antiproliferative and Antimetastatic Activity by Modulating PI3K-Akt and TGF-β-Mediated Downstream Signaling in Prostate Cancer Cells

2021 ◽  
Author(s):  
Abdullah M Alnuqaydan ◽  
Abdulmajeed G Almutary ◽  
Abdullah M Alajlan ◽  
Abdullah Al Tamim ◽  
Abdullah Alowaifeer ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Viability ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Dependent Manner ◽  
Lncap Cells ◽  
Prostate Cancer Cells ◽  
Dose Dependent ◽  
Timp1 Expression ◽  
E Cadherin

Abstract Anticancer drugs mainly kill tumor cells through the apoptosis mechanism, but they can become ineffective when tumor cells are metastatic. Thus, searching for plant-based extracts/compounds to curtail metastasis is extremely important. This study aims to evaluate the anticancer potential of Tamarix articulata (TA) extract against prostate cancer cells. MTT, Brd U, and trypan blue assays was performed to evaluate the cell viability. TUNEL assay were performed to determine apoptotic cells. Clonogenic, wound healing and Boyden chamber assay were conducted to evaluate the anti-clonogenic, anti-motility, and anti-invasive potential of TA. Zymography and immunoblotting were done to check the activity and expression of metalloproteases and proteins associated with metastasis. Our results demonstrated that TA extract significantly inhibits cell viability, clonogenic property, and displays IC₅₀ values in the 245–289 µg/mL range. TA extract significantly abrogates the motility and invasive property of LnCaP cells in a dose-dependent manner. Mechanistically, TA extract downregulates the expression of PI3K-Akt/TGF-β-SMAD2/3 and MMP-2/-9 with concomitant upregulation of TIMP1 expression in LnCaP cells. Additionally, we observe a dose-dependent downregulation of snail and vimentin with the upregulation of E-cadherin protein expression in LnCaP cells. In conclusions, TA extract exhibits an antiproliferative effect, abrogates cell motility and invasion by downregulating PI3K-Akt/TGF-β-SMAD2/3, MMP-2/9, snail, and vimentin with concomitant upregulation of E-cadherin and TIMP1 expression in prostate cancer cells.

1412: Assessment of a Cleaved Product of E-Cadherin as a Serum Biomarker with Predictive Value for Prostate Cancer

2005 ◽  
Vol 173 (4S) ◽  
pp. 383-383
Author(s):  
Rainer Kuefer ◽  
Matthias D. Hofer ◽  
Christoph Zorn ◽  
Bjoern G. Volkmer ◽  
Juergen E. Gschwend ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Predictive Value ◽  
Serum Biomarker ◽  
E Cadherin

410: Cleavage of E-Cadherin and the Role of an 80KDa Fragment in the Metastatic Progression of Prostate Cancer

2004 ◽  
Vol 171 (4S) ◽  
pp. 108-108
Author(s):  
Rainer Kuefer ◽  
Kathleen Day ◽  
Jonathan Rios-Doria ◽  
Matthias Hofer ◽  
Arul Chinnaiyan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Metastatic Progression ◽  
E Cadherin

Expression of Urokinase and Its Receptor in Invasive and Non-Invasive Prostate Cancer Cell Lines

1992 ◽  
Vol 68 (06) ◽  
pp. 662-666 ◽  
Author(s):  
W Hollas ◽  
N Hoosein ◽  
L W K Chung ◽  
A Mazar ◽  
J Henkin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Steady State ◽  
Cell Surface ◽  
Cell Lines ◽  
Cancer Cell ◽  
Prostate Cancer Cell ◽  
Cancer Cell Lines ◽  
Lncap Cells ◽  
Prostate Cancer Cell Lines ◽  
Non Invasive

SummaryWe previously reported that extracellular matrix invasion by the prostate cancer cell lines, PC-3 and DU-145 was contingent on endogenous urokinase being bound to a specific cell surface receptor. The present study was undertaken to characterize the expression of both urokinase and its receptor in the non-invasive LNCaP and the invasive PC-3 and DU-145 prostate cells. Northern blotting indicated that the invasive PC-3 cells, which secreted 10 times more urokinase (680 ng/ml per 106 cells per 48 h) than DU-145 cells (63 ng/ml per 106 cells per 48 h), had the most abundant transcript for the plasminogen activator. This, at least, partly reflected a 3 fold amplification of the urokinase gene in the PC-3 cells. In contrast, urokinase-specific transcript could not be detected in the non-invasive LNCaP cells previously characterized as being negative for urokinase protein. Southern blotting indicated that this was not a consequence of deletion of the urokinase gene. Crosslinking of radiolabelled aminoterminal fragment of urokinase to the cell surface indicated the presence of a 51 kDa receptor in extracts of the invasive PC-3 and DU-145 cells but not in extracts of the non-invasive LNCaP cells. The amount of binding protein correlated well with binding capacities calculated by Scatchard analysis. In contrast, the steady state level of urokinase receptor transcript was a poor predictor of receptor display. PC-3 cells, which were equipped with 25,000 receptors per cell had 2.5 fold more steady state transcript than DU-145 cells which displayed 93,000 binding sites per cell.

Oct1 regulates cell growth of LNCaP cells and is a prognostic factor for prostate cancer

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Prostate Cancer ◽  
Prognostic Factor ◽  
Hazard Analysis ◽  
Critical Role ◽  
Immunohistochemical Analysis ◽  
Lncap Cells ◽  
Cancer Specific Survival ◽  
High Gleason Score ◽  
Castrate Resistant ◽  
Transcription Factor 1

The androgen receptor (AR) plays a critical role in the development and the progression of prostate cancer. Alterations in theexpression of AR coregulators lead to AR hypersensitivity, which is one of the mechanisms underlying the progression ofprostate cancer into a castrate-resistant state. Octamer transcription factor 1 (Oct1) is a ubiquitous member of the POUhomeodomainfamily that functions as a coregulator of AR. In our study, the contribution of Oct1 to prostate cancerdevelopment was examined. Immunocytochemistry analysis showed that Oct1 is expressed in the nuclei of LNCaP cells.siRNA-mediated silencing of Oct1 expression inhibited LNCaP cell proliferation. Immunohistochemical analysis of Oct1expression in tumor specimens obtained from 102 patients with prostate cancer showed a positive correlation of Oct1immunoreactivity with a high Gleason score and AR immunoreactivity (p 5 0.0042 and p &lt; 0.0001, respectively). Moreover,patients with high immunoreactivity of Oct1 showed a low cancer-specific survival rate, and those patients with highimmunoreactivities of both Oct1 and AR exhibited poorer cancer-specific prognosis. Multivariate hazard analysis revealed asignificant correlation between high Oct1 immunoreactivity and poor cancer-specific survival (p 5 0.012). These resultsdemonstrate that Oct1 can be a prognostic factor in prostate cancer as a coregulator of AR and may lead to the developmentof a new therapeutic intervention for prostate cancer.

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