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Molecular Mechanisms Underlying the Progression of Prostate Cancer

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 March 2025 | Viewed by 11671

Special Issue Editors

University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Interests: castration-resistant prostate cancer; epigenetics and epitranscriptomics; transcriptional regulation; chromatin architecture; drug development

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Guest Editor
University of Texas Health Science Center at Houston, Houston, TX 78229, USA
Interests: castration resistance; neuroendocrine prostate cancer; cellular plasticity; epigenetic regulation; hypoxia and angiogenesis

Special Issue Information

Dear Colleagues,

Prostate cancer is the most diagnosed cancer among men in the US, except for skin cancer. It is also the second leading cause of cancer death in American men. Commonly used for patients with metastatic prostate cancer, androgen deprivation therapies (ADTs), which can be achieved by surgical or medical castration to lower androgen levels, have been initially effective. Unfortunately, a majority of prostate tumors invariably relapse and progress to become ADT-resistant, which is referred to as castration-resistant prostate cancer (CRPC). Approximately 20% of lethal metastatic CRPC have a neuroendocrine phenotype following the development of resistance to hormone therapy, and thus are called neuroendocrine prostate cancer (NEPC). NEPC is characterized by low androgen receptor (AR) signaling, castration resistance, and elevated levels of neuroendocrine markers. Unfortunately, without an effective therapy, most patients die within one year upon progression to NEPC. Mechanisms by which prostate cancer progresses to CRPC and further progresses to treatment-emergent NEPC are largely unclear, dramatically hindering the therapeutic development for these lethal forms of the disease.

For this Special Issue, we sincerely invite you to submit research articles or reviews that describe recent advances and novel findings in molecular mechanisms, cell signaling, or biological processes that underlie prostate cancer progression, especially focusing on castration resistance, neuroendocrine differentiation, cellular plasticity, epigenetic regulation, hypoxia and angiogenesis, novel imaging, or therapeutic modalities for NEPC.

Dr. Kexin Xu
Dr. Wenliang Li
Guest Editors

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Keywords

  • prostate cancer progression
  • CRPC
  • NEPC
  • molecular mechanisms
  • cell signaling
  • treatment options

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Published Papers (5 papers)

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Research

22 pages, 5169 KiB  
Article
Pentagalloyl Glucose (PGG) Exhibits Anti-Cancer Activity against Aggressive Prostate Cancer by Modulating the ROR1 Mediated AKT-GSK3β Pathway
by Vignesh Sivaganesh, Tram M. Ta and Bela Peethambaran
Int. J. Mol. Sci. 2024, 25(13), 7003; https://doi.org/10.3390/ijms25137003 - 26 Jun 2024
Viewed by 2420
Abstract
Androgen-receptor-negative, androgen-independent (ARneg-AI) prostate cancer aggressively proliferates and metastasizes, which makes treatment difficult. Hence, it is necessary to continue exploring cancer-associated markers, such as oncofetal Receptor Tyrosine Kinase like Orphan Receptor 1 (ROR1), which may serve as a form of targeted [...] Read more.
Androgen-receptor-negative, androgen-independent (ARneg-AI) prostate cancer aggressively proliferates and metastasizes, which makes treatment difficult. Hence, it is necessary to continue exploring cancer-associated markers, such as oncofetal Receptor Tyrosine Kinase like Orphan Receptor 1 (ROR1), which may serve as a form of targeted prostate cancer therapy. In this study, we identify that Penta-O-galloyl-β-D-glucose (PGG), a plant-derived gallotannin small molecule inhibitor, modulates ROR1-mediated oncogenic signaling and mitigates prostate cancer phenotypes. Results indicate that ROR1 protein levels were elevated in the highly aggressive ARneg-AI PC3 cancer cell line. PGG was selectively cytotoxic to PC3 cells and induced apoptosis of PC3 (IC50 of 31.64 µM) in comparison to normal prostate epithelial RWPE-1 cells (IC50 of 74.55 µM). PGG was found to suppress ROR1 and downstream oncogenic pathways in PC3 cells. These molecular phenomena were corroborated by reduced migration, invasion, and cell cycle progression of PC3 cells. PGG minimally and moderately affected RWPE-1 and ARneg-AI DU145, respectively, which may be due to these cells having lower levels of ROR1 expression in comparison to PC3 cells. Additionally, PGG acted synergistically with the standard chemotherapeutic agent docetaxel to lower the IC50 of both compounds about five-fold (combination index = 0.402) in PC3 cells. These results suggest that ROR1 is a key oncogenic driver and a promising target in aggressive prostate cancers that lack a targetable androgen receptor. Furthermore, PGG may be a selective and potent anti-cancer agent capable of treating ROR1-expressing prostate cancers. Full article
(This article belongs to the Special Issue Molecular Mechanisms Underlying the Progression of Prostate Cancer)
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14 pages, 9810 KiB  
Article
Unveiling the Genomic Landscape of Intraductal Carcinoma of the Prostate Using Spatial Gene Expression Analysis
by Ryuta Watanabe, Noriyoshi Miura, Mie Kurata, Riko Kitazawa, Tadahiko Kikugawa and Takashi Saika
Int. J. Mol. Sci. 2024, 25(9), 4818; https://doi.org/10.3390/ijms25094818 - 28 Apr 2024
Viewed by 1313
Abstract
Intraductal carcinoma of the prostate (IDCP) has recently attracted increasing interest owing to its unfavorable prognoses. To effectively identify the IDCP-specific gene expression profile, we took a novel approach of characterizing a typical IDCP case using spatial gene expression analysis. A formalin-fixed, paraffin-embedded [...] Read more.
Intraductal carcinoma of the prostate (IDCP) has recently attracted increasing interest owing to its unfavorable prognoses. To effectively identify the IDCP-specific gene expression profile, we took a novel approach of characterizing a typical IDCP case using spatial gene expression analysis. A formalin-fixed, paraffin-embedded sample was subjected to Visium CytAssist Spatial Gene Expression analysis. IDCP within invasive prostate cancer sites was recognized as a distinct cluster separate from other invasive cancer clusters. Highly expressed genes defining the IDCP cluster, such as MUC6, MYO16, NPY, and KLK12, reflected the aggressive nature of high-grade prostate cancer. IDCP sites also showed increased hypoxia markers HIF1A, BNIP3L, PDK1, and POGLUT1; decreased fibroblast markers COL1A2, DCN, and LUM; and decreased immune cell markers CCR5 and FCGR3A. Overall, these findings indicate that the hypoxic tumor microenvironment and reduced recruitment of fibroblasts and immune cells, which reflect morphological features of IDCP, may influence the aggressiveness of high-grade prostate cancer. Full article
(This article belongs to the Special Issue Molecular Mechanisms Underlying the Progression of Prostate Cancer)
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21 pages, 2462 KiB  
Article
The Suppression of the Epithelial to Mesenchymal Transition in Prostate Cancer through the Targeting of MYO6 Using MiR-145-5p
by Lee Armstrong, Colin E. Willoughby and Declan J. McKenna
Int. J. Mol. Sci. 2024, 25(8), 4301; https://doi.org/10.3390/ijms25084301 - 12 Apr 2024
Viewed by 1171
Abstract
Aberrant expression of miR-145-5p has been observed in prostate cancer where is has been suggested to play a tumor suppressor role. In other cancers, miR-145-5p acts as an inhibitor of epithelial-to-mesenchymal transition (EMT), a key molecular process for tumor progression. However, the interaction [...] Read more.
Aberrant expression of miR-145-5p has been observed in prostate cancer where is has been suggested to play a tumor suppressor role. In other cancers, miR-145-5p acts as an inhibitor of epithelial-to-mesenchymal transition (EMT), a key molecular process for tumor progression. However, the interaction between miR-145-5p and EMT remains to be elucidated in prostate cancer. In this paper the link between miR-145-5p and EMT in prostate cancer was investigated using a combination of in silico and in vitro analyses. miR-145-5p expression was significantly lower in prostate cancer cell lines compared to normal prostate cells. Bioinformatic analysis of The Cancer Genome Atlas prostate adenocarcinoma (TCGA PRAD) data showed significant downregulation of miR-145-5p in prostate cancer, correlating with disease progression. Functional enrichment analysis significantly associated miR-145-5p and its target genes with EMT. MYO6, an EMT-associated gene, was identified and validated as a novel target of miR-145-5p in prostate cancer cells. In vitro manipulation of miR-145-5p levels significantly altered cell proliferation, clonogenicity, migration and expression of EMT-associated markers. Additional TCGA PRAD analysis suggested miR-145-5p tumor expression may be useful predictor of disease recurrence. In summary, this is the first study to report that miR-145-5p may inhibit EMT by targeting MYO6 in prostate cancer cells. The findings suggest miR-145-5p could be a useful diagnostic and prognostic biomarker for prostate cancer. Full article
(This article belongs to the Special Issue Molecular Mechanisms Underlying the Progression of Prostate Cancer)
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27 pages, 4863 KiB  
Article
Synthesis of Prostate-Specific Membrane Antigen-Targeted Bimodal Conjugates of Cytotoxic Agents and Antiandrogens and Their Comparative Assessment with Monoconjugates
by Nikolai Y. Zyk, Anastasiia S. Garanina, Ekaterina A. Plotnikova, Anton P. Ber, Ekaterina A. Nimenko, Natalia S. Dashkova, Anastasiia A. Uspenskaia, Radik R. Shafikov, Dmitry A. Skvortsov, Stanislav A. Petrov, Andrey A. Pankratov, Nikolai V. Zyk, Alexander G. Majouga, Elena K. Beloglazkina and Aleksei E. Machulkin
Int. J. Mol. Sci. 2023, 24(14), 11327; https://doi.org/10.3390/ijms241411327 - 11 Jul 2023
Cited by 1 | Viewed by 1587
Abstract
Prostate cancer is the second most common cancer among men. We designed and synthesized new ligands targeting prostate-specific membrane antigen and suitable for bimodal conjugates with diagnostic and therapeutic agents. In vitro studies of the affinity of the synthesized compounds to the protein [...] Read more.
Prostate cancer is the second most common cancer among men. We designed and synthesized new ligands targeting prostate-specific membrane antigen and suitable for bimodal conjugates with diagnostic and therapeutic agents. In vitro studies of the affinity of the synthesized compounds to the protein target have been carried out. Based on these ligands, a series of bimodal conjugates with a combination of different mitosis inhibitors and antiandrogenic drugs were synthesized. The cytotoxicity of the compounds obtained in vitro was investigated on three different cell lines. The efficacy of the two obtained conjugates was evaluated in vivo in xenograft models of prostate cancer. These compounds have been shown to be highly effective in inhibiting the growth of PSMA-expressing tumors. Full article
(This article belongs to the Special Issue Molecular Mechanisms Underlying the Progression of Prostate Cancer)
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13 pages, 4652 KiB  
Article
Spatial Gene Expression Analysis Reveals Characteristic Gene Expression Patterns of De Novo Neuroendocrine Prostate Cancer Coexisting with Androgen Receptor Pathway Prostate Cancer
by Ryuta Watanabe, Noriyoshi Miura, Mie Kurata, Riko Kitazawa, Tadahiko Kikugawa and Takashi Saika
Int. J. Mol. Sci. 2023, 24(10), 8955; https://doi.org/10.3390/ijms24108955 - 18 May 2023
Cited by 14 | Viewed by 4447
Abstract
Neuroendocrine prostate carcinoma (NEPC) accounts for less than 1% of prostate neoplasms and has extremely poorer prognosis than the typical androgen receptor pathway-positive adenocarcinoma of the prostate (ARPC). However, very few cases in which de novo NEPC and APRC are diagnosed simultaneously in [...] Read more.
Neuroendocrine prostate carcinoma (NEPC) accounts for less than 1% of prostate neoplasms and has extremely poorer prognosis than the typical androgen receptor pathway-positive adenocarcinoma of the prostate (ARPC). However, very few cases in which de novo NEPC and APRC are diagnosed simultaneously in the same tissue have been reported. We report herein a 78-year-old man of de novo metastatic NEPC coexisting with ARPC treated at Ehime University Hospital. Visium CytAssist Spatial Gene Expression analysis (10× genetics) was performed using formalin-fixed, paraffin-embedded (FFPE) samples. The neuroendocrine signatures were upregulated in NEPC sites, and androgen receptor signatures were upregulated in ARPC sites. TP53, RB1, or PTEN and upregulation of the homologous recombination repair genes at NEPC sites were not downregulated. Urothelial carcinoma markers were not elevated. Meanwhile, Rbfox3 and SFRTM2 levels were downregulated while the levels of the fibrosis markers HGF, HMOX1, ELN, and GREM1 were upregulated in the tumor microenvironment of NEPC. In conclusion, the findings of spatial gene expression analysis in a patient with coexisting ARPC and de novo NEPC are reported. The accumulation of cases and basic data will help with the development of novel treatments for NEPC and improve the prognosis of patients with castration-resistant prostate cancer. Full article
(This article belongs to the Special Issue Molecular Mechanisms Underlying the Progression of Prostate Cancer)
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