Molecular and Cellular Mechanisms of Cancers: Prostate Cancer

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (31 January 2020) | Viewed by 34921

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Laboratory of Radiobiology, Department of Applied Clinical Sciences and Biotechnologies, University of l'Aquila, 67100 L'Aquila, Italy
Interests: prostate cancer
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Guest Editor
Division of Radiotherapy, Department of Applied Clinical Sciences and Biotechnologies, University of L’Aquila, L’Aquila, Italy
Interests: cancer biology; apoptosis; oncology; cancer cells; prostate cancer; radiation oncology; radiotherapy; oncogenes; cancer stem cells
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Prostate cancer (PCa) incidence has been dramatically increasing these last few years in industrialized Western countries. The androgen receptor (AR) plays a central role in the pathogenesis of this disease. Unfortunately, most PCa patients go into an androgen-independent stage named castration-resistant prostate cancer (CRPC) in which AR-signaling still is active. This more aggressive state of disease, in the vast majority of the cases, leads to questions about the molecular mechanisms involving in tumor recurrence. Though localized PCa is usually treated by radical prostatectomy, androgen deprivation therapy (ADT) is preferred in locally advanced disease in combination with chemotherapy.

Inhibition of AR remains, however, a well-established promising drug target in CRPC. However, in spite of the improvements of current treatment for CRPC by targeting the AR, the evolution of adaptive AR-signaling leads to therapy-resistant CRPC. Treatment failure is based mostly on the inability to keep AR under long-term restraint due to adaptive responses of AR-signaling. One underlying mechanism appears to be the increased AR protein stability. Therefore, the regulation of AR protein stability and its degradation is another interesting path that could enhance our knowledge of carcinogenesis and tumor evolution possibly leading to novel therapeutic targets

The main focus of this Special Issue will be the evaluation of molecular pathways as pharmacological targets for treatment strategies which may improve the management of biological aggressive and resistant CRPCs. This Special Issue will provide a platform for all pharmaceutical and translational scientists to learn important breakthroughs in drug discovery and new therapeutics in this field.

 Potential topics include, but are not limit to:

  1. Molecular alterations associated with prostate cancer:

    a) Androgen Receptor: effectiveness and resistance to current pharmacological anti AR approaches;
    b) Targeting mutated ARs and/or splicing variants;
    c) Epigenetic regulation of AR expression: methylation and histone acethylation/deacethylation status, as well as AR protein stability, as targets for the therapy of CRPC and chemotherapy-resistant prostate cancers;
    d) Intra-prostatic androgen synthesis as target for treatment of aggressive/CRPCs (i.e., inhibitors of Cytochrome P450 enzyme CYP17, 17α-hydroxylase and 17,20-lyase, as well as AKR1C3);

  2. Metabolic alterations and PCa progression: cellular constituents of the prostate stroma: key contributors to prostate cancer progression and therapy resistance.

    a) Obesity and mesenchymal stem cells: Key players in prostate cancer progression;
    b) Lipid synthesis and metabolism: i.e., Fatty Acid synthase (FASN) and AMACR;
    c) glutathione metabolism: γ-Glutamylcyclotransferase (GGCT);
    d) Stroma-cancer cell interactions and hypoxia: Stromal niche for epithelial stem cells;
    e) Tumor associated macrophage activation;

  3. Castration resistant metastatic disease (mCRPC)

    a) Epithelial to Mesenchymal Transition (EMT);
    b) VEGF antagonists and VEGFR inhibitors;
    c)Antagonists of integrins (avb3, avb5, a5b1, etc.) and bone metastases;

  4. Mechanisms and strategies to overcome of resistance to radiotherapy or pharmacologic chemotherapy

    a) Radio-sensitizing agents;
    b) Modulators of intracellular trafficking of proteins and mRNA;
    c) antagonists of cell recruitment (Monocytes and granulocytes, Bone Marrow Myeloid cells, PCa stem like cells);
    d) CXCR4/CXCR7 antagonists;
    e) Ephrin/ephrin receptor antagonists or inhibitors;
    f) P21 activated kinases (PAKs);

  5. Inflammation and NF-κB Signaling in Prostate Cancer: Mechanisms and Clinical Implications

  6. Immunomodulators

    Immune Checkpoint-Mediated Interactions Between Cancer and Immune Cells;

  7. Natural compounds

    Papers are published upon acceptance, regardless of the Special Issue publication date.
Prof. Claudio Festuccia
Dr. Francesco Marampon
Guest Editors

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Published Papers (7 papers)

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Research

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15 pages, 2776 KiB  
Article
Elevated NF-κB/SHh/GLI1 Signature Denotes a Worse Prognosis and Represent a Novel Potential Therapeutic Target in Advanced Prostate Cancer
by Davide Vecchiotti, Daniela Verzella, Mauro Di Vito Nolfi, Daniel D’Andrea, Irene Flati, Barbara Di Francesco, Jessica Cornice, Edoardo Alesse, Daria Capece and Francesca Zazzeroni
Cells 2022, 11(13), 2118; https://doi.org/10.3390/cells11132118 - 5 Jul 2022
Cited by 11 | Viewed by 2180
Abstract
Prostate cancer (PCa) is the second most frequent cancer in men worldwide. NF-κB seems to play a key role in cell survival, proliferation and invasion, sustaining the heterogeneous multifocal nature of PCa. In recent years, the Hedgehog (Hh) signaling pathway has attracted attention [...] Read more.
Prostate cancer (PCa) is the second most frequent cancer in men worldwide. NF-κB seems to play a key role in cell survival, proliferation and invasion, sustaining the heterogeneous multifocal nature of PCa. In recent years, the Hedgehog (Hh) signaling pathway has attracted attention as a therapeutic target due to its implication in tumorigenesis and metastasis in several types of cancer, including PCa. Although it is well-known that Sonic Hedgehog (SHh) is a transcriptional target of NF-κB(p65), and that GLI1 is the effector of this crosstalk, the precise role played by this axis in PCa is still not completely clear. Here, we set out to explore the correlation between NF-κB activation and SHh pathways in PCa, investigating if the interplay between NF-κB(p65) and SHh-GLI1 in advanced PCa could be a prospective therapeutic target. Our findings demonstrate that a NF-κB-SHh-GLI1 gene signature is enriched in PCa patients featuring a higher Gleason score. Moreover, elevated levels of this signature are associated with worse prognosis, thus suggesting that this axis could provide a route to treat aggressive PCa. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Prostate Cancer)
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17 pages, 4696 KiB  
Article
miR-1272 Exerts Tumor-Suppressive Functions in Prostate Cancer via HIP1 Suppression
by Federica Rotundo, Denis Cominetti, Rihan El Bezawy, Stefano Percio, Valentina Doldi, Monica Tortoreto, Valentina Zuco, Riccardo Valdagni, Nadia Zaffaroni and Paolo Gandellini
Cells 2020, 9(2), 435; https://doi.org/10.3390/cells9020435 - 13 Feb 2020
Cited by 11 | Viewed by 3140
Abstract
The development of novel therapies or the improvement of currently used approaches to treat prostate cancer (PCa), the most frequently diagnosed male tumor in developed countries, is an urgent need. In this regard, the functional characterization of microRNAs, molecules shown to regulate a [...] Read more.
The development of novel therapies or the improvement of currently used approaches to treat prostate cancer (PCa), the most frequently diagnosed male tumor in developed countries, is an urgent need. In this regard, the functional characterization of microRNAs, molecules shown to regulate a number of cancer-related pathways, is instrumental to their possible clinical exploitation. Here, we demonstrate the tumor-suppressive role of the so far uncharacterized miR-1272, which we found to be significantly down-modulated in PCa clinical specimens compared to normal tissues. Through a gain-of-function approach using miRNA mimics, we showed that miR-1272 supplementation in two PCa cell models (DU145 and 22Rv1) reverted the mesenchymal phenotype by affecting migratory and invasive properties, and reduced cell growth in vitro and in vivo in SCID mice. Additionally, by targeting HIP1 encoding the endocytic protein HIP1, miR-1272 balanced EGFR membrane turnover, thus affecting the downstream AKT/ERK pathways, and, ultimately, increasing PCa cell response to ionizing radiation. Overall, our results show that miR-1272 reconstitution can affect several tumor traits, thus suggesting this approach as a potential novel therapeutic strategy to be pursued for PCa, with the multiple aim of reducing tumor growth, enhancing response to radiotherapy and limiting metastatic dissemination. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Prostate Cancer)
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32 pages, 7808 KiB  
Article
Dual CXCR4 and E-Selectin Inhibitor, GMI-1359, Shows Anti-Bone Metastatic Effects and Synergizes with Docetaxel in Prostate Cancer Cell Intraosseous Growth
by Claudio Festuccia, Andrea Mancini, Giovanni Luca Gravina, Alessandro Colapietro, Antonella Vetuschi, Simona Pompili, Luca Ventura, Simona Delle Monache, Roberto Iorio, Andrea Del Fattore, William Fogler and John Magnani
Cells 2020, 9(1), 32; https://doi.org/10.3390/cells9010032 - 20 Dec 2019
Cited by 20 | Viewed by 4757
Abstract
Metastatic castration resistant prostate cancer (mCRPC) relapses due to acquired resistance to docetaxel-based chemotherapy and remains a major threat to patient survival. In this report, we tested the effectiveness of a dual CXCR4/E-selectin antagonist, GM-I1359, in vitro and in vivo, as a single [...] Read more.
Metastatic castration resistant prostate cancer (mCRPC) relapses due to acquired resistance to docetaxel-based chemotherapy and remains a major threat to patient survival. In this report, we tested the effectiveness of a dual CXCR4/E-selectin antagonist, GM-I1359, in vitro and in vivo, as a single agent or in combination with docetaxel (DTX). This agent was compared to the single CXCR4 antagonist, CTCE-9908, and E-selectin antagonist, GMI-1271. Here we demonstrate that CXCR4 antagonism reduced growth and enhanced DTX treatment in PCa cell lines as well as restored DTX effectiveness in DTX-resistant cell models. The efficacy of dual antagonist was higher respect to those observed for single CXCR4 antagonism. GM1359 impacted bone marrow colonization and growth in intraventricular and intratibial cell injection models. The anti-proliferative effects of GMI-1359 and DTX correlated with decreased size, osteolysis and serum levels of both mTRAP and type I collagen fragment (CTX) in intra-osseous tumours suggesting that the dual CXCR4/E-selectin antagonist was a docetaxel-sensitizing agent for bone metastatic growth. Single agent CXCR4 (CTCE-9908) and E-selectin (GMI-1271) antagonists resulted in lower sensitizing effects compared to GMI-1359. These data provide a biologic rationale for the use of a dual E-selectin/CXCR4 inhibitor as an adjuvant to taxane-based chemotherapy in men with mCRPC to prevent and reduce bone metastases. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Prostate Cancer)
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20 pages, 7369 KiB  
Article
Shmt2: A Stat3 Signaling New Player in Prostate Cancer Energy Metabolism
by Ilaria Marrocco, Fabio Altieri, Elisabetta Rubini, Giuliano Paglia, Silvia Chichiarelli, Flavia Giamogante, Alberto Macone, Giacomo Perugia, Fabio Massimo Magliocca, Aymone Gurtner, Bruno Maras, Rino Ragno, Alexandros Patsilinakos, Roberto Manganaro and Margherita Eufemi
Cells 2019, 8(9), 1048; https://doi.org/10.3390/cells8091048 - 6 Sep 2019
Cited by 28 | Viewed by 6418
Abstract
Prostate cancer (PCa) is a multifactorial disease characterized by the aberrant activity of different regulatory pathways. STAT3 protein mediates some of these pathways and its activation is implicated in the modulation of several metabolic enzymes. A bioinformatic analysis indicated a STAT3 binding site [...] Read more.
Prostate cancer (PCa) is a multifactorial disease characterized by the aberrant activity of different regulatory pathways. STAT3 protein mediates some of these pathways and its activation is implicated in the modulation of several metabolic enzymes. A bioinformatic analysis indicated a STAT3 binding site in the upstream region of SHMT2 gene. We demonstrated that in LNCaP, PCa cells’ SHMT2 expression is upregulated by the JAK2/STAT3 canonical pathway upon IL-6 stimulation. Activation of SHTM2 leads to a decrease in serine levels, pushing PKM2 towards the nuclear compartment where it can activate STAT3 in a non-canonical fashion that in turn promotes a transient shift toward anaerobic metabolism. These results were also confirmed on FFPE prostate tissue sections at different Gleason scores. STAT3/SHMT2/PKM2 loop in LNCaP cells can modulate a metabolic shift in response to inflammation at early stages of cancer progression, whereas a non-canonical STAT3 activation involving the STAT3/HIF-1α/PKM2 loop is responsible for the maintenance of Warburg effect distinctive of more aggressive PCa cells. Chronic inflammation might thus prime the transition of PCa cells towards more advanced stages, and SHMT2 could represent a missing factor to further understand the molecular mechanisms responsible for the transition of prostate cancer towards a more aggressive phenotype. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Prostate Cancer)
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Review

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15 pages, 1450 KiB  
Review
Necroptosis and Prostate Cancer: Molecular Mechanisms and Therapeutic Potential
by Giovanni Luca Beretta and Nadia Zaffaroni
Cells 2022, 11(7), 1221; https://doi.org/10.3390/cells11071221 - 4 Apr 2022
Cited by 20 | Viewed by 3910
Abstract
Necroptosis is a programmed form of necrosis characterized by mitochondrial alterations and plasma membrane permeabilization resulting in the release of cytoplasmic content into extracellular space, and leading to inflammatory reactions. Besides its critical role in viral defense mechanisms and inflammatory diseases, necroptosis plays [...] Read more.
Necroptosis is a programmed form of necrosis characterized by mitochondrial alterations and plasma membrane permeabilization resulting in the release of cytoplasmic content into extracellular space, and leading to inflammatory reactions. Besides its critical role in viral defense mechanisms and inflammatory diseases, necroptosis plays pivotal functions in the drug response of tumors, including prostate cancer. Necroptosis is mainly governed by kinase enzymes, including RIP1, RIP3, and MLKL, and conversely to apoptosis, is a caspase-independent mechanism of cell death. Numerous compounds induce necroptosis in prostate cancer models, including (i) compounds of natural origin, (ii) synthetic and semisynthetic small molecules, and (iii) selenium and selenium-based nanoparticles. Here, we overview the molecular mechanisms underlying necroptosis and discuss the possible implications of drugs inducing necroptosis for prostate cancer therapy. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Prostate Cancer)
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31 pages, 1299 KiB  
Review
Natural Compounds in Prostate Cancer Prevention and Treatment: Mechanisms of Action and Molecular Targets
by Fabrizio Fontana, Michela Raimondi, Monica Marzagalli, Alessandro Di Domizio and Patrizia Limonta
Cells 2020, 9(2), 460; https://doi.org/10.3390/cells9020460 - 18 Feb 2020
Cited by 65 | Viewed by 8861
Abstract
Prostate cancer (PCa) represents a major cause of cancer mortality among men in developed countries. Patients with recurrent disease initially respond to androgen-deprivation therapy, but the tumor eventually progresses into castration-resistant PCa; in this condition, tumor cells acquire the ability to escape cell [...] Read more.
Prostate cancer (PCa) represents a major cause of cancer mortality among men in developed countries. Patients with recurrent disease initially respond to androgen-deprivation therapy, but the tumor eventually progresses into castration-resistant PCa; in this condition, tumor cells acquire the ability to escape cell death and develop resistance to current therapies. Thus, new therapeutic approaches for PCa management are urgently needed. In this setting, natural products have been extensively studied for their anti-PCa activities, such as tumor growth suppression, cell death induction, and inhibition of metastasis and angiogenesis. Additionally, numerous studies have shown that phytochemicals can specifically target the androgen receptor (AR) signaling, as well as the PCa stem cells (PCSCs). Interestingly, many clinical trials have been conducted to test the efficacy of nutraceuticals in human subjects, and they have partially confirmed the promising results obtained in vitro and in preclinical models. This article summarizes the anti-cancer mechanisms and therapeutic potentials of different natural compounds in the context of PCa prevention and treatment. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Prostate Cancer)
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15 pages, 1448 KiB  
Review
Molecular Mechanisms Related to Hormone Inhibition Resistance in Prostate Cancer
by Veronica Mollica, Vincenzo Di Nunno, Alessia Cimadamore, Antonio Lopez-Beltran, Liang Cheng, Matteo Santoni, Marina Scarpelli, Rodolfo Montironi and Francesco Massari
Cells 2019, 8(1), 43; https://doi.org/10.3390/cells8010043 - 11 Jan 2019
Cited by 37 | Viewed by 4643
Abstract
Management of metastatic or advanced prostate cancer has acquired several therapeutic approaches that have drastically changed the course of the disease. In particular due to the high sensitivity of prostate cancer cells to hormone depletion, several agents able to inhibit hormone production or [...] Read more.
Management of metastatic or advanced prostate cancer has acquired several therapeutic approaches that have drastically changed the course of the disease. In particular due to the high sensitivity of prostate cancer cells to hormone depletion, several agents able to inhibit hormone production or binding to nuclear receptor have been evaluated and adopted in clinical practice. However, despite several hormonal treatments being available nowadays for the management of advanced or metastatic prostate cancer, the natural history of the disease leads inexorably to the development of resistance to hormone inhibition. Findings regarding the mechanisms that drive this process are of particular and increasing interest as these are potentially related to the identification of new targetable pathways and to the development of new drugs able to improve our patients’ clinical outcomes. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Prostate Cancer)
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