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26 pages, 10208 KiB

Open AccessArticle

Radioresistance Mechanisms in Prostate Cancer Cell Lines Surviving Ultra-Hypo-Fractionated EBRT: Implications and Possible Clinical Applications

by Silvia Sideri, Francesco Petragnano, Roberto Maggio, Simonetta Petrungaro, Angela Catizone, Luisa Gesualdi, Viviana De Martino, Giulia Battafarano, Andrea Del Fattore, Domenico Liguoro, Paola De Cesaris, Antonio Filippini, Francesco Marampon and Anna Riccioli

Cancers 2022, 14(22), 5504; https://doi.org/10.3390/cancers14225504 - 9 Nov 2022

Cited by 1 | Viewed by 2070

Abstract

The use of a higher dose per fraction to overcome the high radioresistance of prostate cancer cells has been unsuccessfully proposed. Herein, we present PC3 and DU-145, castration-resistant prostate cancer cell lines that survived a clinically used ultra-higher dose per fraction, namely, radioresistant [...] Read more.

The use of a higher dose per fraction to overcome the high radioresistance of prostate cancer cells has been unsuccessfully proposed. Herein, we present PC3 and DU-145, castration-resistant prostate cancer cell lines that survived a clinically used ultra-higher dose per fraction, namely, radioresistant PC3 and DU-145 cells (PC3RR and DU-145RR). Compared to PC3, PC3RR showed a higher level of aggressive behaviour, with enhanced clonogenic potential, DNA damage repair, migration ability and cancer stem cell features. Furthermore, compared to PC3, PC3RR more efficiently survived further radiation by increasing proliferation and down-regulating pro-apoptotic proteins. No significant changes of the above parameters were described in DU-145RR, suggesting that different prostate cancer cell lines that survive ultra-higher dose per fraction do not display the same grade of aggressive phenotype. Furthermore, both PC3RR and DU-145RR increased antioxidant enzymes and mesenchymal markers. Our data suggest that different molecular mechanisms could be potential targets for future treatments plans based on sequential strategies and synergistic effects of different modalities, possibly in a patient-tailored fashion. Moreover, PC3RR cells displayed an increase in specific markers involved in bone remodeling, indicating that radiotherapy selects a PC3 population capable of migrating to secondary metastatic sites. Finally, PC3RR cells showed a better sensitivity to Docetaxel as compared to native PC3 cells. This suggests that a subset of patients with castration-resistant metastatic disease could benefit from upfront Docetaxel treatment after the failure of radiotherapy. Full article

(This article belongs to the Special Issue Models, Mechanisms, and Biomarkers of Prostate Cancer Progression)

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23 pages, 3903 KiB

Open AccessArticle

The Potential Tumor-Suppressor DHRS7 Inversely Correlates with EGFR Expression in Prostate Cancer Cells and Tumor Samples

by Simon Stücheli, Selene Araya, Caner Ercan, Seraina O. Moser, John Gallon, Paul Jenö, Salvatore Piscuoglio, Luigi Terracciano and Alex Odermatt

Cancers 2022, 14(13), 3074; https://doi.org/10.3390/cancers14133074 - 23 Jun 2022

Cited by 2 | Viewed by 2688

Abstract

Prostate cancer (PCa), one of the most common malignancies in men, typically responds to initial treatment, but resistance to therapy often leads to metastases and death. The dehydrogenase/reductase 7 (DHRS7, SDR34C1) is an “orphan” enzyme without known physiological function. DHRS7 was previously found [...] Read more.

Prostate cancer (PCa), one of the most common malignancies in men, typically responds to initial treatment, but resistance to therapy often leads to metastases and death. The dehydrogenase/reductase 7 (DHRS7, SDR34C1) is an “orphan” enzyme without known physiological function. DHRS7 was previously found to be decreased in higher-stage PCa, and siRNA-mediated knockdown increased the aggressiveness of LNCaP cells. To further explore the role of DHRS7 in PCa, we analyzed the proteome of LNCaP cells following DHRS7 knockdown to assess potentially altered pathways. Although DHRS7 is able to inactivate 5α-dihydrotestosterone, DHRS7 knockdown did not affect androgen receptor (AR) target gene expression, and its effect on PCa cells seems to be androgen-independent. Importantly, proteome analyses revealed increased expression of epidermal growth factor receptor (EGFR), which was confirmed by RT-qPCR and Western blotting. Comparison of AR-positive LNCaP with AR-negative PC-3 and DU145 PCa cell lines revealed a negative correlation between DHRS7 and EGFR expression. Conversely, EGFR knockdown enhanced DHRS7 expression in these cells. Importantly, analysis of patient samples revealed a negative correlation between DHRS7 and EGFR expression, both at the mRNA and protein levels, and DHRS7 expression correlated positively with patient survival rates. These results suggest a protective role for DHRS7 in PCa. Full article

(This article belongs to the Special Issue Models, Mechanisms, and Biomarkers of Prostate Cancer Progression)

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19 pages, 3532 KiB

Open AccessArticle

TR3 Enhances AR Variant Production and Transactivation, Promoting Androgen Independence of Prostate Cancer Cells

by Tuyen Thanh Tran and Keesook Lee

Cancers 2022, 14(8), 1911; https://doi.org/10.3390/cancers14081911 - 10 Apr 2022

Cited by 3 | Viewed by 2043

Abstract

The pro-oncogenic function of TR3, an orphan nuclear receptor, has been reported in prostate cancer. However, the roles of TR3 in androgen receptor (AR) expression and signaling in prostate cancer cells are poorly understood. Database analysis revealed that TR3 expression level is elevated [...] Read more.

The pro-oncogenic function of TR3, an orphan nuclear receptor, has been reported in prostate cancer. However, the roles of TR3 in androgen receptor (AR) expression and signaling in prostate cancer cells are poorly understood. Database analysis revealed that TR3 expression level is elevated in prostate tumors, and is positively, although weakly, correlated with that of AR. TR3 overexpression increased the production of AR splice variants in addition to general upregulation of AR expression. TR3 interacted with some spliceosomal complex components and AR precursor mRNA, altering the splice junction rates between exons. TR3 also enhanced androgen-independent AR function. Furthermore, TR3 overexpression increased cell proliferation and mobility of AR-positive prostate cancer cells and stimulated tumorigenesis of androgen-independent prostate cancer cells in mouse xenograft models. This is the first study to report that TR3 is a multifunctional regulator of AR signaling in prostate cancer cells. TR3 alters AR expression, splicing process, and activity in prostate cancer cells, increasing the androgen independence of AR signaling. Therefore, TR3 may play a crucial role in the progression of prostate cancer to an advanced castration-resistant form. Full article

(This article belongs to the Special Issue Models, Mechanisms, and Biomarkers of Prostate Cancer Progression)

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22 pages, 6208 KiB

Open AccessArticle

Increased Expression and Altered Cellular Localization of Fibroblast Growth Factor Receptor-Like 1 (FGFRL1) Are Associated with Prostate Cancer Progression

by Lan Yu, Mervi Toriseva, Syeda Afshan, Mario Cangiano, Vidal Fey, Andrew Erickson, Heikki Seikkula, Kalle Alanen, Pekka Taimen, Otto Ettala, Martti Nurmi, Peter J. Boström, Markku Kallajoki, Johanna Tuomela, Tuomas Mirtti, Inès J. Beumer, Matthias Nees and Pirkko Härkönen

Cancers 2022, 14(2), 278; https://doi.org/10.3390/cancers14020278 - 7 Jan 2022

Cited by 4 | Viewed by 3003

Abstract

Fibroblast growth factor receptors (FGFRs) 1–4 are involved in prostate cancer (PCa) regulation, but the role of FGFR-like 1 (FGFRL1) in PCa is unclear. FGFRL1 expression was studied by qRT-PCR and immunohistochemistry of patient tissue microarrays (TMAs) and correlated with clinical patient data. [...] Read more.

Fibroblast growth factor receptors (FGFRs) 1–4 are involved in prostate cancer (PCa) regulation, but the role of FGFR-like 1 (FGFRL1) in PCa is unclear. FGFRL1 expression was studied by qRT-PCR and immunohistochemistry of patient tissue microarrays (TMAs) and correlated with clinical patient data. The effects of FGFRL1 knockdown (KD) in PC3M were studied in in vitro culture models and in mouse xenograft tumors. Our results showed that FGFRL1 was significantly upregulated in PCa. The level of membranous FGFRL1 was negatively associated with high Gleason scores (GSs) and Ki67, while increased cytoplasmic and nuclear FGFRL1 showed a positive correlation. Cox regression analysis indicated that nuclear FGFRL1 was an independent prognostic marker for biochemical recurrence after radical prostatectomy. Functional studies indicated that FGFRL1-KD in PC3M cells increases FGFR signaling, whereas FGFRL1 overexpression attenuates it, supporting decoy receptor actions of membrane-localized FGFRL1. In accordance with clinical data, FGFRL1-KD markedly suppressed PC3M xenograft growth. Transcriptomics of FGFRL1-KD cells and xenografts revealed major changes in genes regulating differentiation, ECM turnover, and tumor–stromal interactions associated with decreased growth in FGFRL1-KD xenografts. Our results suggest that FGFRL1 upregulation and altered cellular compartmentalization contribute to PCa progression. The nuclear FGFRL1 could serve as a prognostic marker for PCa patients. Full article

(This article belongs to the Special Issue Models, Mechanisms, and Biomarkers of Prostate Cancer Progression)

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14 pages, 3049 KiB

Open AccessArticle

Characterization of Novel Progression Factors in Castration-Resistant Prostate Cancer Based on Global Comparative Proteome Analysis

by Ann-Yae Na, Soyoung Choi, Eunju Yang, Kwang-Hyeon Liu, Sunghwan Kim, Hyun Jin Jung, Youngshik Choe, Yun-Sok Ha, Tae Gyun Kwon, Jun Nyung Lee and Sangkyu Lee

Cancers 2021, 13(14), 3432; https://doi.org/10.3390/cancers13143432 - 8 Jul 2021

Cited by 4 | Viewed by 2563

Abstract

Identifying the biological change from hormone-naïve prostate cancer to castration-resistant prostate cancer (CRPC) is a major clinical challenge for developing therapeutic agents. Although the pathways that lead to CRPC are not fully completely understood, recent evidence demonstrates that androgen signaling is often maintained [...] Read more.

Identifying the biological change from hormone-naïve prostate cancer to castration-resistant prostate cancer (CRPC) is a major clinical challenge for developing therapeutic agents. Although the pathways that lead to CRPC are not fully completely understood, recent evidence demonstrates that androgen signaling is often maintained through varied mechanisms. Androgen deprivation therapy (ADT) is used as a primary treatment for preventing the progression of prostate cancer (PCa). Here we investigated PCa tissues at each stage of progression, from benign prostatic hyperplasia (BPH) to CRPC, based on quantitative proteomic technology, including tissues after ADT. In total, 4768 proteins were identified in this study, of which 4069 were quantified in the combined PCa tissues. Among the quantified proteins, 865 were differentially expressed proteins (21.2%). Based on the quantitative protein results, we performed systematic bioinformatics analysis and found that the levels of 15 proteins, including FOXA1 and HMGN1–3, increased among T3G3, T3GX, and CRPC, despite the ADT. Among all targets, we verified the increased levels of FOXA1 and HMGN1–3 in CRPC by immunoblotting and indirect enzyme-linked immunosorbent assay. In summary, we discuss the changes in intracellular factors involved in the progression of CRPC PCa despite ADT. Moreover, we suggest that FOXA1 and HMGN1–3 proteins could be used as potential CRPC-related factors in clinical therapeutic agents. Full article

(This article belongs to the Special Issue Models, Mechanisms, and Biomarkers of Prostate Cancer Progression)

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Review

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28 pages, 3450 KiB

Open AccessReview

Lactate as Key Metabolite in Prostate Cancer Progression: What Are the Clinical Implications?

by Paolo Chetta, Renuka Sriram and Giorgia Zadra

Cancers 2023, 15(13), 3473; https://doi.org/10.3390/cancers15133473 - 3 Jul 2023

Cited by 7 | Viewed by 2836

Abstract

Advanced prostate cancer represents the fifth leading cause of cancer death in men worldwide. Although androgen-receptor signaling is the major driver of the disease, evidence is accumulating that disease progression is supported by substantial metabolic changes. Alterations in de novo lipogenesis and fatty [...] Read more.

Advanced prostate cancer represents the fifth leading cause of cancer death in men worldwide. Although androgen-receptor signaling is the major driver of the disease, evidence is accumulating that disease progression is supported by substantial metabolic changes. Alterations in de novo lipogenesis and fatty acid catabolism are consistently reported during prostate cancer development and progression in association with androgen-receptor signaling. Therefore, the term “lipogenic phenotype” is frequently used to describe the complex metabolic rewiring that occurs in prostate cancer. However, a new scenario has emerged in which lactate may play a major role. Alterations in oncogenes/tumor suppressors, androgen signaling, hypoxic conditions, and cells in the tumor microenvironment can promote aerobic glycolysis in prostate cancer cells and the release of lactate in the tumor microenvironment, favoring immune evasion and metastasis. As prostate cancer is composed of metabolically heterogenous cells, glycolytic prostate cancer cells or cancer-associated fibroblasts can also secrete lactate and create “symbiotic” interactions with oxidative prostate cancer cells via lactate shuttling to sustain disease progression. Here, we discuss the multifaceted role of lactate in prostate cancer progression, taking into account the influence of the systemic metabolic and gut microbiota. We call special attention to the clinical opportunities of imaging lactate accumulation for patient stratification and targeting lactate metabolism. Full article

(This article belongs to the Special Issue Models, Mechanisms, and Biomarkers of Prostate Cancer Progression)

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20 pages, 11380 KiB

Open AccessReview

The Extracellular Matrix Stiffening: A Trigger of Prostate Cancer Progression and Castration Resistance?

by Carole Luthold, Tarek Hallal, David P. Labbé and François Bordeleau

Cancers 2022, 14(12), 2887; https://doi.org/10.3390/cancers14122887 - 11 Jun 2022

Cited by 20 | Viewed by 5210

Abstract

Despite advancements made in diagnosis and treatment, prostate cancer remains the second most diagnosed cancer among men worldwide in 2020, and the first in North America and Europe. Patients with localized disease usually respond well to first-line treatments, however, up to 30% develop [...] Read more.

Despite advancements made in diagnosis and treatment, prostate cancer remains the second most diagnosed cancer among men worldwide in 2020, and the first in North America and Europe. Patients with localized disease usually respond well to first-line treatments, however, up to 30% develop castration-resistant prostate cancer (CRPC), which is often metastatic, making this stage of the disease incurable and ultimately fatal. Over the last years, interest has grown into the extracellular matrix (ECM) stiffening as an important mediator of diseases, including cancers. While this process is increasingly well-characterized in breast cancer, a similar in-depth look at ECM stiffening remains lacking for prostate cancer. In this review, we scrutinize the current state of literature regarding ECM stiffening in prostate cancer and its potential association with disease progression and castration resistance. Full article

(This article belongs to the Special Issue Models, Mechanisms, and Biomarkers of Prostate Cancer Progression)

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26 pages, 1216 KiB

Open AccessReview

Intraductal Carcinoma of the Prostate as a Cause of Prostate Cancer Metastasis: A Molecular Portrait

by Helen Pantazopoulos, Mame-Kany Diop, Andrée-Anne Grosset, Frédérique Rouleau-Gagné, Afnan Al-Saleh, Teodora Boblea and Dominique Trudel

Cancers 2022, 14(3), 820; https://doi.org/10.3390/cancers14030820 - 6 Feb 2022

Cited by 13 | Viewed by 10003

Abstract

Intraductal carcinoma of the prostate (IDC-P) is one of the most aggressive types of prostate cancer (PCa). IDC-P is identified in approximately 20% of PCa patients and is associated with recurrence, metastasis, and PCa-specific death. The main feature of this histological variant is [...] Read more.

Intraductal carcinoma of the prostate (IDC-P) is one of the most aggressive types of prostate cancer (PCa). IDC-P is identified in approximately 20% of PCa patients and is associated with recurrence, metastasis, and PCa-specific death. The main feature of this histological variant is the colonization of benign glands by PCa cells. Although IDC-P is a well-recognized independent parameter for metastasis, mechanisms by which IDC-P cells can spread and colonize other tissues are not fully known. In this review, we discuss the molecular portraits of IDC-P determined by immunohistochemistry and genomic approaches and highlight the areas in which more research is needed. Full article

(This article belongs to the Special Issue Models, Mechanisms, and Biomarkers of Prostate Cancer Progression)

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