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Biomedicines
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Signaling Pathways and Targeted Molecular Therapy in Prostate Cancer
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Signaling Pathways and Targeted Molecular Therapy in Prostate Cancer

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Gene and Cell Therapy".

Deadline for manuscript submissions: closed (15 September 2022) | Viewed by 11315

Special Issue Editor

Dr. Filippos Koinis

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Guest Editor
Laboratory of Oncology, University of Thessaly Mezourlo, Larissa, Thessaly, Greece
Interests: prostate cancer; small cell lung cancer; cells; signaling pathways

Special Issue Information

Dear Colleagues,

Prostate cancer (PCa) is a leading cause of cancer morbidity and mortality in men worldwide. Prostate cancer development is associated with several risk factors, such as older age, black ethnicity, a family history of disease, increased body mass index, and obesity. Despite the fact that numerous approaches are available for the treatment of prostate cancer, the number of prostate cancer deaths is continuously increasing, which emphasizes the need to search for new methods for more effective treatment.

In the meantime, the multiple mechanisms of resistance to molecularly targeted therapy need to be described. The aim of this Special Issue is to publish a collection of papers on signaling pathways in the pathogenesis of prostate cancer and the methods and molecular mechanisms of targeted therapy.

Dr. Filippos Koinis
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Prostate cancer
  • target treatment
  • signaling pathways
  • biomarkers
  • pathogenesis

Published Papers (5 papers)

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Research

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10 pages, 1584 KiB  
Article
Portrait of Molecular Signaling and Putative Therapeutic Targets in Prostate Cancer with ETV4 Fusion
by Ye Ji Shin, Jae Won Yun and Hong Sook Kim
Biomedicines 2022, 10(10), 2650; https://doi.org/10.3390/biomedicines10102650 - 20 Oct 2022
Viewed by 1397
Abstract
Gene fusion between androgen receptor (AR) response genes and E26 transformation-specific (ETS) family members increases the gene expression of ETS family members, and promotes tumorigenesis in prostate cancer. However, the molecular features of ETV4 fusion in prostate cancer are not fully understood, and [...] Read more.
Gene fusion between androgen receptor (AR) response genes and E26 transformation-specific (ETS) family members increases the gene expression of ETS family members, and promotes tumorigenesis in prostate cancer. However, the molecular features of ETV4 fusion in prostate cancer are not fully understood, and drugs targeting ETV4 fusion have not been developed. To examine key cellular signaling pathways and explore therapeutic targets and drugs for ETV4-fusion-positive prostate cancer, we analyzed RNA sequencing data and clinical information for prostate cancer. The ETV4-fusion-positive group was selected through prior study and analysis comparing ETV4-fusion-positive and -negative groups was conducted using a Pearson correlation test. We obtained 393 genes correlated with ETV4 expression. Pathway analysis was performed using over-representation analysis (ORA), and six cancer-specific molecular signaling pathways (the irinotecan pathway, metabolism, androgen receptor signaling, interferon signaling, MAPK/NF-kB signaling, and the tamoxifen pathway) were altered in the ETV4-fusion-positive group. Furthermore, a gene–drug database was used to find an actionable drug and therapeutic target for the ETV4-fusion-positive group. Here, we have identified significantly altered genes and oncogenic signaling pathways in ETV4-fusion-positive prostate cancer, and we suggest therapeutic targets and potential drugs for ETV4-fusion-positive prostate patients. Full article
(This article belongs to the Special Issue Signaling Pathways and Targeted Molecular Therapy in Prostate Cancer)
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15 pages, 2887 KiB  
Article
CARD14 Signalling Ensures Cell Survival and Cancer Associated Gene Expression in Prostate Cancer Cells
by Domien Vanneste, Jens Staal, Mira Haegman, Yasmine Driege, Marieke Carels, Elien Van Nuffel, Pieter De Bleser, Yvan Saeys, Rudi Beyaert and Inna S. Afonina
Biomedicines 2022, 10(8), 2008; https://doi.org/10.3390/biomedicines10082008 - 18 Aug 2022
Cited by 3 | Viewed by 2211
Abstract
Prostate cancer (PCa) is one of the most common cancer types in men and represents an increasing global problem due to the modern Western lifestyle. The signalling adapter protein CARD14 is specifically expressed in epithelial cells, where it has been shown to mediate [...] Read more.
Prostate cancer (PCa) is one of the most common cancer types in men and represents an increasing global problem due to the modern Western lifestyle. The signalling adapter protein CARD14 is specifically expressed in epithelial cells, where it has been shown to mediate NF-κB signalling, but a role for CARD14 in carcinoma has not yet been described. By analysing existing cancer databases, we found that CARD14 overexpression strongly correlates with aggressive PCa in human patients. Moreover, we showed that CARD14 is overexpressed in the LNCaP PCa cell line and that knockdown of CARD14 severely reduces LNCaP cell survival. Similarly, knockdown of BCL10 and MALT1, which are known to form a signalling complex with CARD14, also induced LNCaP cell death. MALT1 is a paracaspase that mediates downstream signalling by acting as a scaffold, as well as a protease. Recent studies have already indicated a role for the scaffold function of MALT1 in PCa cell growth. Here, we also demonstrated constitutive MALT1 proteolytic activity in several PCa cell lines, leading to cleavage of A20 and CYLD. Inhibition of MALT1 protease activity did not affect PCa cell survival nor activation of NF-κB and JNK signalling, but reduced expression of cancer-associated genes, including the cytokine IL-6. Taken together, our results revealed a novel role for CARD14-induced signalling in regulating PCa cell survival and gene expression. The epithelial cell type-specific expression of CARD14 may offer novel opportunities for more specific therapeutic targeting approaches in PCa. Full article
(This article belongs to the Special Issue Signaling Pathways and Targeted Molecular Therapy in Prostate Cancer)
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16 pages, 2935 KiB  
Article
Characterization of Proteins Regulated by Androgen and Protein Kinase a Signaling in VCaP Prostate Cancer Cells
by Hye-Jin You, Byong-Chul You, Jong-Kwang Kim, Jae-Min Park, Bo-Seul Song and Jae-Kyung Myung
Biomedicines 2021, 9(10), 1404; https://doi.org/10.3390/biomedicines9101404 - 06 Oct 2021
Cited by 2 | Viewed by 1956
Abstract
Androgen signaling via the androgen receptor (AR) is involved in normal prostate development and prostate cancer progression. In addition to androgen binding, a variety of protein kinases, including cyclic AMP-dependent protein kinase A (PKA), can activate the AR. Although hormone deprivation, especially that [...] Read more.
Androgen signaling via the androgen receptor (AR) is involved in normal prostate development and prostate cancer progression. In addition to androgen binding, a variety of protein kinases, including cyclic AMP-dependent protein kinase A (PKA), can activate the AR. Although hormone deprivation, especially that of androgen, continues to be an important strategy for treating prostate cancer patients, the disease ultimately progresses to castration-resistant prostate cancer (CRPC), despite a continuous hormone-deprived environment. To date, it remains unclear which pathways in this progression are active and targetable. Here, we performed a proteomic analysis of VCaP cells stimulated with androgen or forskolin to identify proteins specific for androgen-induced and androgen-bypassing signaling, respectively. Patterns of differentially expressed proteins were quantified, and eight proteins showing significant changes in expression were identified. Functional information, including a Gene Ontology analysis, revealed that most of these proteins are involved in metabolic processes and are associated with cancer. The mRNA and protein expression of selected proteins was validated, and functional correlations of identified proteins with signaling in VCaP cells were assessed by measuring metabolites related to each enzyme. These analyses offered new clues regarding effector molecules involved in prostate cancer development, insights that are supported by the demonstration of increased expression levels of the eight identified proteins in prostate cancer patients and assessments of the progression-free interval. Taken together, our findings show that aberrant levels of eight proteins reflect molecular changes that are significantly regulated by androgen and/or PKA signaling pathways, suggesting possible molecular mechanisms of CRPC. Full article
(This article belongs to the Special Issue Signaling Pathways and Targeted Molecular Therapy in Prostate Cancer)
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22 pages, 56179 KiB  
Article
Concomitant High Apoptosis Inhibitor of Macrophage (AIM) and Low Prostate-Specific Antigen (PSA) Indicates Activated T Cell-Mediated Anticancer Immunity, Enhance Sensitivity to Pembrolizumab, and Elicit Good Prognosis in Prostate Cancer
by Oluwaseun Adebayo Bamodu, Yuan-Hung Wang, Chi-Tai Yeh, Chen-Hsun Ho, Yi-Te Chiang, Wei-Tang Kao, Chia-Hung Liu and Chia-Chang Wu
Biomedicines 2021, 9(9), 1225; https://doi.org/10.3390/biomedicines9091225 - 15 Sep 2021
Cited by 4 | Viewed by 2634
Abstract
Background: Despite its widespread use, the use of prostate-specific antigen (PSA) alone as a screening biomarker for prostate cancer (PCa) leads often to unwarranted prostate biopsy, over-diagnosis, and consequently, over-treatment, because of its limited specificity. There are reports that the apoptosis inhibitor of [...] Read more.
Background: Despite its widespread use, the use of prostate-specific antigen (PSA) alone as a screening biomarker for prostate cancer (PCa) leads often to unwarranted prostate biopsy, over-diagnosis, and consequently, over-treatment, because of its limited specificity. There are reports that the apoptosis inhibitor of macrophage (AIM), secreted mainly by macrophages and epithelial cells, is upregulated during inflammation and facilitates immune recognition of cancerous cells by blocking human regulator of complement activation. Objective: These controversies around the PSA utility necessitate a reexamination of its use as a screening tool. More so, despite the suggested implication of AIM in anticancer immunosurveillance, there is a dearth of information on its role in therapy response, disease progression, and clinical outcomes of patients with PCa. These inform the present study to probe the nature and role of AIM/PSA signaling in anticancer immunity and prognosis in PCa. Methods: A combination of bioinformatics-aided statistical analyses, gene function annotation, and immune infiltrate analyses, coupled with tissue staining, and function assays, namely migration, invasion, and clonogenicity assays, we employed. Results: We demonstrated that AIM and PSA expression levels are inversely correlated in PCa clinical samples and cell lines, with AIMlowPSAhigh defining PCa, compared to AIMhighPSAlow in normal samples. Concomitant aberrant PSA and significantly suppressed AIM expression levels positively correlated with high-grade disease and characterized by advanced stage prostate cancer, regardless of mutation status. We found that a high PSA/AIM ratio is associated with disease recurrence in patients with prostate cancer but is equivocal for overall survival. In addition, PSA-associated AIM suppression is implicated in the enhanced ‘metastability’ of PCa and a high AIM/PSA ratio is associated with strong castration-induced regression. CRISPR-mediated AIM knockout was associated with higher PSA expression while ectopic expression of AIM significantly attenuated the migration and invasive capability of PC3 and DU145 cells. Interestingly, compared to normal samples, we observed that AIM, biomarkers of T-cell activation and M1 phenotype markers are co-suppressed in PCa samples. Conclusion: Herein, we demonstrate that AIM/CD5L binds to PSA and that a high PSA/AIM ratio defines advanced stage PCa (regardless of mutation status), is implicated in enhanced metastability, and associated with disease recurrence, while a high AIM/PSA ratio is associated with strong castration-induced regression. More so, the ectopic expression of AIM significantly enhances the anticancer effect of Pembrolizumab and elicits an increased CD8+ T-cell count in AIMhiPSAloPDL1+ PCa cases that are respondent to Pembrolizumab treatment. Full article
(This article belongs to the Special Issue Signaling Pathways and Targeted Molecular Therapy in Prostate Cancer)
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Review

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18 pages, 1060 KiB  
Review
Emerging Role of YAP and the Hippo Pathway in Prostate Cancer
by Filippos Koinis, Evangelia Chantzara, Michael Samarinas, Anastasia Xagara, Zisis Kratiras, Vasiliki Leontopoulou and Athanasios Kotsakis
Biomedicines 2022, 10(11), 2834; https://doi.org/10.3390/biomedicines10112834 - 07 Nov 2022
Cited by 3 | Viewed by 2079
Abstract
The Hippo pathway regulates and contributes to several hallmarks of prostate cancer (PCa). Although the elucidation of YAP function in PCa is in its infancy, emerging studies have shed light on the role of aberrant Hippo pathway signaling in PCa development and progression. [...] Read more.
The Hippo pathway regulates and contributes to several hallmarks of prostate cancer (PCa). Although the elucidation of YAP function in PCa is in its infancy, emerging studies have shed light on the role of aberrant Hippo pathway signaling in PCa development and progression. YAP overexpression and nuclear localization has been linked to poor prognosis and resistance to treatment, highlighting a therapeutic potential that may suggest innovative strategies to treat cancer. This review aimed to summarize available data on the biological function of the dysregulated Hippo pathway in PCa and identify knowledge gaps that need to be addressed for optimizing the development of YAP-targeted treatment strategies in patients likely to benefit. Full article
(This article belongs to the Special Issue Signaling Pathways and Targeted Molecular Therapy in Prostate Cancer)
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