scholarly journals Targeting Mitochondrial OXPHOS and Their Regulatory Signals in Prostate Cancers

2021 ◽  
Vol 22 (24) ◽  
pp. 13435
Author(s):  
Chia-Lin Chen ◽  
Ching-Yu Lin ◽  
Hsing-Jien Kung
Keyword(s):  
Prostate Cancer ◽  
Energy Demand ◽  
Metabolic Regulation ◽  
Seminal Fluid ◽  
Genetic Regulation ◽  
Tumor Development ◽  
Tca Cycle ◽  
Current Status ◽  
Normal Prostate ◽  
Primary Tumors

Increasing evidence suggests that tumor development requires not only oncogene/tumor suppressor mutations to drive the growth, survival, and metastasis but also metabolic adaptations to meet the increasing energy demand for rapid cellular expansion and to cope with the often nutritional and oxygen-deprived microenvironment. One well-recognized strategy is to shift the metabolic flow from oxidative phosphorylation (OXPHOS) or respiration in mitochondria to glycolysis or fermentation in cytosol, known as Warburg effects. However, not all cancer cells follow this paradigm. In the development of prostate cancer, OXPHOS actually increases as compared to normal prostate tissue. This is because normal prostate epithelial cells divert citrate in mitochondria for the TCA cycle to the cytosol for secretion into seminal fluid. The sustained level of OXPHOS in primary tumors persists in progression to an advanced stage. As such, targeting OXPHOS and mitochondrial activities in general present therapeutic opportunities. In this review, we summarize the recent findings of the key regulators of the OXPHOS pathway in prostate cancer, ranging from transcriptional regulation, metabolic regulation to genetic regulation. Moreover, we provided a comprehensive update of the current status of OXPHOS inhibitors for prostate cancer therapy. A challenge of developing OXPHOS inhibitors is to selectively target cancer mitochondria and spare normal counterparts, which is also discussed.

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.

scholarly journals Reducing Selenoprotein F Promotes the Transformation of Immortalized Prostate Epithelial Cells

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1809-1809
Author(s):  
Lenny Hong ◽  
Mostafa Elhodaky ◽  
Shrinidhi Kadkol ◽  
Alan Diamond
Keyword(s):  
Prostate Cancer ◽  
Epithelial Cells ◽  
Cancer Progression ◽  
Tca Cycle ◽  
Soft Agar ◽  
Metabolic Shift ◽  
Normal Prostate ◽  
Funding Sources ◽  
Prostate Cells ◽  
Prostate Epithelial Cells

Abstract Objectives Selenoprotein F (SELENOF) levels are responsive to available dietary selenium and found in high levels in benign prostate cells. It is implicated in prostate cancer (PCa) mortality due to associations between polymorphisms in the corresponding gene and death from the disease. SELENOF levels are dramatically lower in prostate cancer compared to adjacent benign tissue. The objective of this study was to determine whether reducing SELENOF levels in human, non-transformed RWPE-1 prostate epithelial cells alters their phenotype to implicate SELENOF loss in PCa progression. Methods SELENOF levels were reduced in RWPE-1 cells that express high levels of SELENOF using a SELENOF shRNA construct. Proliferation was determined by quantifying DNA using fluorometric dsDNA quantitation. Growth in soft agar and cell mobility of cells in culture (wound healing assay) were imaged using an Evos FL microscope and quantified using Image J software. The oxygen consumption rate (OCR) was measured using a Seahorse XFe24 Analyzer. Results SELENOF levels were reduced in RWPE-1 and these cells exhibited decreased contact inhibition in culture (n = 3, P < 0.001) when compared to controls. Normal prostate epithelial cells are atypical in that they rely on glycolysis for energy production, have a truncated TCA cycle, and a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS) occurs in PCa. Reducing SELENOF in RWPE-1 cells resulted in higher OCR compared to controls, indicating that SELENOF can impact the sources and pathways used in cellular energy metabolism. Conclusions Reduced SELENOF levels in RWPE-1 prostate cells resulted in properties consistent with a transformed phenotype and an increase in OCR, and indicating that the reduction in SELENOF may contribute a metabolic shift towards a PCa cancer-like metabolism. Together, these results indicate that SELENOF loss likely contributes to cancer progression. Funding Sources This work was supported by a grant from the Department of Defense to AMD and a Pre-Doctoral Education for Clinical and Translational Scientists Fellowship to LKH.

scholarly journals Circulating extracellular vesicles release oncogenic miR-424 in experimental models and patients with aggressive prostate cancer

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Domenico Albino ◽  
Martina Falcione ◽  
Valeria Uboldi ◽  
Dada Oluwaseyi Temilola ◽  
Giada Sandrini ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Epithelial Cells ◽  
Cancer Patients ◽  
Extracellular Vesicles ◽  
Disease Recurrence ◽  
Experimental Models ◽  
Normal Prostate ◽  
Primary Tumors ◽  
Disease Evolution ◽  
Prostate Epithelial Cells

AbstractExtracellular vesicles (EVs) are relevant means for transferring signals across cells and facilitate propagation of oncogenic stimuli promoting disease evolution and metastatic spread in cancer patients. Here, we investigated the release of miR-424 in circulating small EVs or exosomes from prostate cancer patients and assessed the functional implications in multiple experimental models. We found higher frequency of circulating miR-424 positive EVs in patients with metastatic prostate cancer compared to patients with primary tumors and BPH. Release of miR-424 in small EVs was enhanced in cell lines (LNCaPabl), transgenic mice (Pb-Cre4;Ptenflox/flox;Rosa26ERG/ERG) and patient-derived xenograft (PDX) models of aggressive disease. EVs containing miR-424 promoted stem-like traits and tumor-initiating properties in normal prostate epithelial cells while enhanced tumorigenesis in transformed prostate epithelial cells. Intravenous administration of miR-424 positive EVs to mice, mimicking blood circulation, promoted miR-424 transfer and tumor growth in xenograft models. Circulating miR-424 positive EVs from patients with aggressive primary and metastatic tumors induced stem-like features when supplemented to prostate epithelial cells. This study establishes that EVs-mediated transfer of miR-424 across heterogeneous cell populations is an important mechanism of tumor self-sustenance, disease recurrence and progression. These findings might indicate novel approaches for the management and therapy of prostate cancer.

scholarly journals The AR/NCOA1 axis regulates prostate cancer migration by involvement of PRKD1

2016 ◽  
Vol 23 (6) ◽  
pp. 495-508 ◽  
Author(s):  
Birgit Luef ◽  
Florian Handle ◽  
Gvantsa Kharaishvili ◽  
Martina Hager ◽  
Johannes Rainer ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cellular Migration ◽  
Migration And Invasion ◽  
Strong Increase ◽  
Final Conclusion ◽  
Boyden Chamber ◽  
Normal Prostate ◽  
Primary Tumors ◽  
Normal Prostate Tissue ◽  
Pc3 Cells

Due to the urgent need for new prostate cancer (PCa) therapies, the role of androgen receptor (AR)-interacting proteins should be investigated. In this study we aimed to address whether the AR coactivator nuclear receptor coactivator 1 (NCOA1) is involved in PCa progression. Therefore, we tested the effect of long-termNCOA1knockdown on processes relevant to metastasis formation. [3H]-thymidine incorporation assays revealed a reduced proliferation rate in AR-positive MDA PCa 2b and LNCaP cells upon knockdown ofNCOA1, whereas AR-negative PC3 cells were not affected. Furthermore, Boyden chamber assays showed a strong decrease in migration and invasion uponNCOA1knockdown, independently of the cell line’s AR status. In order to understand the mechanistic reasons for these changes, transcriptome analysis using cDNA microarrays was performed. Protein kinase D1 (PRKD1) was found to be prominently up-regulated byNCOA1knockdown in MDA PCa 2b, but not in PC3 cells. Inhibition ofPRKD1reverted the reduced migratory potential caused byNCOA1knockdown. Furthermore, PRKD1 was negatively regulated by AR. Immunohistochemical staining of PCa patient samples revealed a strong increase in NCOA1 expression in primary tumors compared with normal prostate tissue, while no final conclusion could be drawn for PRKD1 expression in tumor specimens. Thus, our findings directly associate the AR/NCOA1 complex withPRKD1regulation and cellular migration and support the concept of therapeutic inhibition of NCOA1 in PCa.

scholarly journals The Transcriptomic Landscape of Prostate Cancer Development and Progression: An Integrative Analysis

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 345
Author(s):  
Jacek Marzec ◽  
Helen Ross-Adams ◽  
Stefano Pirrò ◽  
Jun Wang ◽  
Yanan Zhu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Metastatic Disease ◽  
Prognostic Significance ◽  
Intraepithelial Neoplasia ◽  
Analytical Framework ◽  
Molecular Profile ◽  
Mrna Levels ◽  
Normal Prostate ◽  
Primary Tumors ◽  
Disease Stages

Next-generation sequencing of primary tumors is now standard for transcriptomic studies, but microarray-based data still constitute the majority of available information on other clinically valuable samples, including archive material. Using prostate cancer (PC) as a model, we developed a robust analytical framework to integrate data across different technical platforms and disease subtypes to connect distinct disease stages and reveal potentially relevant genes not identifiable from single studies alone. We reconstructed the molecular profile of PC to yield the first comprehensive insight into its development, by tracking changes in mRNA levels from normal prostate to high-grade prostatic intraepithelial neoplasia, and metastatic disease. A total of nine previously unreported stage-specific candidate genes with prognostic significance were also found. Here, we integrate gene expression data from disparate sample types, disease stages and technical platforms into one coherent whole, to give a global view of the expression changes associated with the development and progression of PC from normal tissue through to metastatic disease. Summary and individual data are available online at the Prostate Integrative Expression Database (PIXdb), a user-friendly interface designed for clinicians and laboratory researchers to facilitate translational research.

scholarly journals Opposing Roles of Dnmt1 in Early- and Late-Stage Murine Prostate Cancer

2010 ◽  
Vol 30 (17) ◽  
pp. 4159-4174 ◽  
Author(s):  
Shannon R. Morey Kinney ◽  
Michael T. Moser ◽  
Marien Pascual ◽  
John M. Greally ◽  
Barbara A. Foster ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Late Stage ◽  
Early Stage ◽  
Tumor Incidence ◽  
Dna Hypomethylation ◽  
Dna Hypermethylation ◽  
Normal Prostate ◽  
Early Stage Disease ◽  
Primary Tumors ◽  
Stage Disease

ABSTRACT Previous studies have shown that tumor progression in the transgenic adenocarcinoma of mouse prostate (TRAMP) model is characterized by global DNA hypomethylation initiated during early-stage disease and locus-specific DNA hypermethylation occurring predominantly in late-stage disease. Here, we utilized Dnmt1 hypomorphic alleles to examine the role of Dnmt1 in normal prostate development and in prostate cancer in TRAMP. Prostate tissue morphology and differentiation status was normal in Dnmt1 hypomorphic mice, despite global DNA hypomethylation. TRAMP; Dnmt1 hypomorphic mice also displayed global DNA hypomethylation, but were characterized by altered tumor phenotype. Specifically, TRAMP; Dnmt1 hypomorphic mice exhibited slightly increased tumor incidence and significantly increased pathological progression at early ages and, conversely, displayed slightly decreased tumor incidence and significantly decreased pathological progression at advanced ages. Remarkably, hypomorphic Dnmt1 expression abrogated local and distant site macrometastases. Thus, Dnmt1 has tumor suppressor activity in early-stage prostate cancer, and oncogenic activity in late stage prostate cancer and metastasis. Consistent with the biological phenotype, epigenomic studies revealed that TRAMP; Dnmt1 hypomorphic mice show dramatically reduced CpG island and promoter DNA hypermethylation in late-stage primary tumors compared to control mice. Taken together, the data reveal a crucial role for Dnmt1 in prostate cancer and suggest that Dnmt1-targeted interventions may have utility specifically for advanced and/or metastatic prostate cancer.

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