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Loss of Fibroblast-Dependent Androgen Receptor Activation in Prostate Cancer Cells is Involved in the Mechanism of Acquired Resistance to Castration
Loss of androgen receptor (AR) dependency in prostate cancer (PCa) cells is associated with progression to castration-resistant prostate cancer (CRPC). The tumor stroma is enriched in fibroblasts that secrete AR-activating factors. To investigate the roles of fibroblasts in AR activation under andro...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780155/ https://www.ncbi.nlm.nih.gov/pubmed/31484364 http://dx.doi.org/10.3390/jcm8091379 |
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author | Ishii, Kenichiro Matsuoka, Izumi Sasaki, Takeshi Nishikawa, Kohei Kanda, Hideki Imai, Hiroshi Hirokawa, Yoshifumi Iguchi, Kazuhiro Arima, Kiminobu Sugimura, Yoshiki |
author_facet | Ishii, Kenichiro Matsuoka, Izumi Sasaki, Takeshi Nishikawa, Kohei Kanda, Hideki Imai, Hiroshi Hirokawa, Yoshifumi Iguchi, Kazuhiro Arima, Kiminobu Sugimura, Yoshiki |
author_sort | Ishii, Kenichiro |
collection | PubMed |
description | Loss of androgen receptor (AR) dependency in prostate cancer (PCa) cells is associated with progression to castration-resistant prostate cancer (CRPC). The tumor stroma is enriched in fibroblasts that secrete AR-activating factors. To investigate the roles of fibroblasts in AR activation under androgen deprivation, we used three sublines of androgen-sensitive LNCaP cells (E9 and F10 cells: low androgen sensitivity; and AIDL cells: androgen insensitivity) and original fibroblasts derived from patients with PCa. We performed in vivo experiments using three sublines of LNCaP cells and original fibroblasts to form homotypic tumors. The volume of tumors derived from E9 cells plus fibroblasts was reduced following androgen deprivation therapy (ADT), whereas that of F10 or AIDL cells plus fibroblasts was increased even after ADT. In tumors derived from E9 cells plus fibroblasts, serum prostate-specific antigen (PSA) decreased rapidly after ADT, but was still detectable. In contrast, serum PSA was increased even in F10 cells inoculated alone. In indirect cocultures with fibroblasts, PSA production was increased in E9 cells. Epidermal growth factor treatment stimulated Akt and p44/42 mitogen-activated protein kinase phosphorylation in E9 cells. Notably, AR splice variant 7 was detected in F10 cells. Overall, we found that fibroblast-secreted AR-activating factors modulated AR signaling in E9 cells after ADT and loss of fibroblast-dependent AR activation in F10 cells may be responsible for CRPC progression. |
format | Online Article Text |
id | pubmed-6780155 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-67801552019-10-30 Loss of Fibroblast-Dependent Androgen Receptor Activation in Prostate Cancer Cells is Involved in the Mechanism of Acquired Resistance to Castration Ishii, Kenichiro Matsuoka, Izumi Sasaki, Takeshi Nishikawa, Kohei Kanda, Hideki Imai, Hiroshi Hirokawa, Yoshifumi Iguchi, Kazuhiro Arima, Kiminobu Sugimura, Yoshiki J Clin Med Article Loss of androgen receptor (AR) dependency in prostate cancer (PCa) cells is associated with progression to castration-resistant prostate cancer (CRPC). The tumor stroma is enriched in fibroblasts that secrete AR-activating factors. To investigate the roles of fibroblasts in AR activation under androgen deprivation, we used three sublines of androgen-sensitive LNCaP cells (E9 and F10 cells: low androgen sensitivity; and AIDL cells: androgen insensitivity) and original fibroblasts derived from patients with PCa. We performed in vivo experiments using three sublines of LNCaP cells and original fibroblasts to form homotypic tumors. The volume of tumors derived from E9 cells plus fibroblasts was reduced following androgen deprivation therapy (ADT), whereas that of F10 or AIDL cells plus fibroblasts was increased even after ADT. In tumors derived from E9 cells plus fibroblasts, serum prostate-specific antigen (PSA) decreased rapidly after ADT, but was still detectable. In contrast, serum PSA was increased even in F10 cells inoculated alone. In indirect cocultures with fibroblasts, PSA production was increased in E9 cells. Epidermal growth factor treatment stimulated Akt and p44/42 mitogen-activated protein kinase phosphorylation in E9 cells. Notably, AR splice variant 7 was detected in F10 cells. Overall, we found that fibroblast-secreted AR-activating factors modulated AR signaling in E9 cells after ADT and loss of fibroblast-dependent AR activation in F10 cells may be responsible for CRPC progression. MDPI 2019-09-03 /pmc/articles/PMC6780155/ /pubmed/31484364 http://dx.doi.org/10.3390/jcm8091379 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Ishii, Kenichiro Matsuoka, Izumi Sasaki, Takeshi Nishikawa, Kohei Kanda, Hideki Imai, Hiroshi Hirokawa, Yoshifumi Iguchi, Kazuhiro Arima, Kiminobu Sugimura, Yoshiki Loss of Fibroblast-Dependent Androgen Receptor Activation in Prostate Cancer Cells is Involved in the Mechanism of Acquired Resistance to Castration |
title | Loss of Fibroblast-Dependent Androgen Receptor Activation in Prostate Cancer Cells is Involved in the Mechanism of Acquired Resistance to Castration |
title_full | Loss of Fibroblast-Dependent Androgen Receptor Activation in Prostate Cancer Cells is Involved in the Mechanism of Acquired Resistance to Castration |
title_fullStr | Loss of Fibroblast-Dependent Androgen Receptor Activation in Prostate Cancer Cells is Involved in the Mechanism of Acquired Resistance to Castration |
title_full_unstemmed | Loss of Fibroblast-Dependent Androgen Receptor Activation in Prostate Cancer Cells is Involved in the Mechanism of Acquired Resistance to Castration |
title_short | Loss of Fibroblast-Dependent Androgen Receptor Activation in Prostate Cancer Cells is Involved in the Mechanism of Acquired Resistance to Castration |
title_sort | loss of fibroblast-dependent androgen receptor activation in prostate cancer cells is involved in the mechanism of acquired resistance to castration |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780155/ https://www.ncbi.nlm.nih.gov/pubmed/31484364 http://dx.doi.org/10.3390/jcm8091379 |
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