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Osteoblasts Promote Prostate Cancer Cell Proliferation Through Androgen Receptor Independent Mechanisms
Patients with metastatic prostate cancer frequently develop bone metastases that elicit significant skeletal morbidity and increased mortality. The high tropism of prostate cancer cells for bone and their tendency to induce the osteoblastic-like phenotype are a result of a complex interplay between...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8711264/ https://www.ncbi.nlm.nih.gov/pubmed/34966687 http://dx.doi.org/10.3389/fonc.2021.789885 |
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author | Ribelli, Giulia Simonetti, Sonia Iuliani, Michele Rossi, Elisabetta Vincenzi, Bruno Tonini, Giuseppe Pantano, Francesco Santini, Daniele |
author_facet | Ribelli, Giulia Simonetti, Sonia Iuliani, Michele Rossi, Elisabetta Vincenzi, Bruno Tonini, Giuseppe Pantano, Francesco Santini, Daniele |
author_sort | Ribelli, Giulia |
collection | PubMed |
description | Patients with metastatic prostate cancer frequently develop bone metastases that elicit significant skeletal morbidity and increased mortality. The high tropism of prostate cancer cells for bone and their tendency to induce the osteoblastic-like phenotype are a result of a complex interplay between tumor cells and osteoblasts. Although the role of osteoblasts in supporting prostate cancer cell proliferation has been reported by previous studies, their precise contribution in tumor growth remains to be fully elucidated. Here, we tried to dissect the molecular signaling underlining the interactions between castration-resistant prostate cancer (CRPC) cells and osteoblasts using in vitro co-culture models. Transcriptomic analysis showed that osteoblast-conditioned media (OCM) induced the overexpression of genes related to cell cycle in the CRPC cell line C4-2B but, surprisingly, reduced androgen receptor (AR) transcript levels. In-depth analysis of AR expression in C4-2B cells after OCM treatment showed an AR reduction at the mRNA (p = 0.0047), protein (p = 0.0247), and functional level (p = 0.0029) and, concomitantly, an increase of C4-2B cells in S-G2-M cell cycle phases (p = 0.0185). An extensive proteomic analysis revealed in OCM the presence of some molecules that reduced AR activation, and among these, Matrix metalloproteinase-1 (MMP-1) was the only one able to block AR function (0.1 ng/ml p = 0.006; 1 ng/ml p = 0.002; 10 ng/ml p = 0.0001) and, at the same time, enhance CRPC proliferation (1 ng/ml p = 0.009; 10 ng/ml p = 0.033). Although the increase of C4-2B cell growth induced by MMP-1 did not reach the proliferation levels observed after OCM treatment, the addition of Vorapaxar, an MMP-1 receptor inhibitor (Protease-activated receptor-1, PAR-1), significantly reduced C4-2B cell cycle (0.1 μM p = 0.014; 1 μM p = 0.0087). Overall, our results provide a novel AR-independent mechanism of CRPC proliferation and suggest that MMP-1/PAR-1 could be one of the potential pathways involved in this process. |
format | Online Article Text |
id | pubmed-8711264 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-87112642021-12-28 Osteoblasts Promote Prostate Cancer Cell Proliferation Through Androgen Receptor Independent Mechanisms Ribelli, Giulia Simonetti, Sonia Iuliani, Michele Rossi, Elisabetta Vincenzi, Bruno Tonini, Giuseppe Pantano, Francesco Santini, Daniele Front Oncol Oncology Patients with metastatic prostate cancer frequently develop bone metastases that elicit significant skeletal morbidity and increased mortality. The high tropism of prostate cancer cells for bone and their tendency to induce the osteoblastic-like phenotype are a result of a complex interplay between tumor cells and osteoblasts. Although the role of osteoblasts in supporting prostate cancer cell proliferation has been reported by previous studies, their precise contribution in tumor growth remains to be fully elucidated. Here, we tried to dissect the molecular signaling underlining the interactions between castration-resistant prostate cancer (CRPC) cells and osteoblasts using in vitro co-culture models. Transcriptomic analysis showed that osteoblast-conditioned media (OCM) induced the overexpression of genes related to cell cycle in the CRPC cell line C4-2B but, surprisingly, reduced androgen receptor (AR) transcript levels. In-depth analysis of AR expression in C4-2B cells after OCM treatment showed an AR reduction at the mRNA (p = 0.0047), protein (p = 0.0247), and functional level (p = 0.0029) and, concomitantly, an increase of C4-2B cells in S-G2-M cell cycle phases (p = 0.0185). An extensive proteomic analysis revealed in OCM the presence of some molecules that reduced AR activation, and among these, Matrix metalloproteinase-1 (MMP-1) was the only one able to block AR function (0.1 ng/ml p = 0.006; 1 ng/ml p = 0.002; 10 ng/ml p = 0.0001) and, at the same time, enhance CRPC proliferation (1 ng/ml p = 0.009; 10 ng/ml p = 0.033). Although the increase of C4-2B cell growth induced by MMP-1 did not reach the proliferation levels observed after OCM treatment, the addition of Vorapaxar, an MMP-1 receptor inhibitor (Protease-activated receptor-1, PAR-1), significantly reduced C4-2B cell cycle (0.1 μM p = 0.014; 1 μM p = 0.0087). Overall, our results provide a novel AR-independent mechanism of CRPC proliferation and suggest that MMP-1/PAR-1 could be one of the potential pathways involved in this process. Frontiers Media S.A. 2021-12-13 /pmc/articles/PMC8711264/ /pubmed/34966687 http://dx.doi.org/10.3389/fonc.2021.789885 Text en Copyright © 2021 Ribelli, Simonetti, Iuliani, Rossi, Vincenzi, Tonini, Pantano and Santini https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Ribelli, Giulia Simonetti, Sonia Iuliani, Michele Rossi, Elisabetta Vincenzi, Bruno Tonini, Giuseppe Pantano, Francesco Santini, Daniele Osteoblasts Promote Prostate Cancer Cell Proliferation Through Androgen Receptor Independent Mechanisms |
title | Osteoblasts Promote Prostate Cancer Cell Proliferation Through Androgen Receptor Independent Mechanisms |
title_full | Osteoblasts Promote Prostate Cancer Cell Proliferation Through Androgen Receptor Independent Mechanisms |
title_fullStr | Osteoblasts Promote Prostate Cancer Cell Proliferation Through Androgen Receptor Independent Mechanisms |
title_full_unstemmed | Osteoblasts Promote Prostate Cancer Cell Proliferation Through Androgen Receptor Independent Mechanisms |
title_short | Osteoblasts Promote Prostate Cancer Cell Proliferation Through Androgen Receptor Independent Mechanisms |
title_sort | osteoblasts promote prostate cancer cell proliferation through androgen receptor independent mechanisms |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8711264/ https://www.ncbi.nlm.nih.gov/pubmed/34966687 http://dx.doi.org/10.3389/fonc.2021.789885 |
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