Inhibition of FOXC2 restores epithelial phenotype and drug sensitivity in prostate cancer cells with stem-cell properties

Advanced prostate adenocarcinomas enriched in stem-cell features, as well as variant androgen receptor (AR)-negative neuroendocrine (NE)/small-cell prostate cancers are difficult to treat, and account for up to 30% of prostate cancer-related deaths every year. While existing therapies for prostate c...

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Main Authors:	Paranjape, A N, Soundararajan, R, Werden, S J, Joseph, R, Taube, J H, Liu, H, Rodriguez-Canales, J, Sphyris, N, Wistuba, I, Miura, N, Dhillon, J, Mahajan, N, Mahajan, K, Chang, J T, Ittmann, M, Maity, S N, Logothetis, C, Tang, D G, Mani, S A
Format:	Online
Language:	English
Published:	Nature Publishing Group 2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5116559/

id	pubmed-5116559
recordtype	oai_dc
spelling	pubmed-51165592016-12-16 Inhibition of FOXC2 restores epithelial phenotype and drug sensitivity in prostate cancer cells with stem-cell properties Paranjape, A N Soundararajan, R Werden, S J Joseph, R Taube, J H Liu, H Rodriguez-Canales, J Sphyris, N Wistuba, I Miura, N Dhillon, J Mahajan, N Mahajan, K Chang, J T Ittmann, M Maity, S N Logothetis, C Tang, D G Mani, S A Original Article Advanced prostate adenocarcinomas enriched in stem-cell features, as well as variant androgen receptor (AR)-negative neuroendocrine (NE)/small-cell prostate cancers are difficult to treat, and account for up to 30% of prostate cancer-related deaths every year. While existing therapies for prostate cancer such as androgen deprivation therapy (ADT), destroy the bulk of the AR-positive cells within the tumor, eradicating this population eventually leads to castration-resistance, owing to the continued survival of AR-/lo stem-like cells. In this study, we identified a critical nexus between p38MAPK signaling, and the transcription factor Forkhead Box Protein C2 (FOXC2) known to promote cancer stem-cells and metastasis. We demonstrate that prostate cancer cells that are insensitive to ADT, as well as high-grade/NE prostate tumors, are characterized by elevated FOXC2, and that targeting FOXC2 using a well-tolerated p38 inhibitor restores epithelial attributes and ADT-sensitivity, and reduces the shedding of circulating tumor cells in vivo with significant shrinkage in the tumor mass. This study thus specifies a tangible mechanism to target the AR-/lo population of prostate cancer cells with stem-cell properties. Nature Publishing Group 2016-11-17 2016-01-25 /pmc/articles/PMC5116559/ /pubmed/26804168 http://dx.doi.org/10.1038/onc.2015.498 Text en Copyright © 2016 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Paranjape, A N Soundararajan, R Werden, S J Joseph, R Taube, J H Liu, H Rodriguez-Canales, J Sphyris, N Wistuba, I Miura, N Dhillon, J Mahajan, N Mahajan, K Chang, J T Ittmann, M Maity, S N Logothetis, C Tang, D G Mani, S A
spellingShingle	Paranjape, A N Soundararajan, R Werden, S J Joseph, R Taube, J H Liu, H Rodriguez-Canales, J Sphyris, N Wistuba, I Miura, N Dhillon, J Mahajan, N Mahajan, K Chang, J T Ittmann, M Maity, S N Logothetis, C Tang, D G Mani, S A Inhibition of FOXC2 restores epithelial phenotype and drug sensitivity in prostate cancer cells with stem-cell properties
author_facet	Paranjape, A N Soundararajan, R Werden, S J Joseph, R Taube, J H Liu, H Rodriguez-Canales, J Sphyris, N Wistuba, I Miura, N Dhillon, J Mahajan, N Mahajan, K Chang, J T Ittmann, M Maity, S N Logothetis, C Tang, D G Mani, S A
author_sort	Paranjape, A N
title	Inhibition of FOXC2 restores epithelial phenotype and drug sensitivity in prostate cancer cells with stem-cell properties
title_short	Inhibition of FOXC2 restores epithelial phenotype and drug sensitivity in prostate cancer cells with stem-cell properties
title_full	Inhibition of FOXC2 restores epithelial phenotype and drug sensitivity in prostate cancer cells with stem-cell properties
title_fullStr	Inhibition of FOXC2 restores epithelial phenotype and drug sensitivity in prostate cancer cells with stem-cell properties
title_full_unstemmed	Inhibition of FOXC2 restores epithelial phenotype and drug sensitivity in prostate cancer cells with stem-cell properties
title_sort	inhibition of foxc2 restores epithelial phenotype and drug sensitivity in prostate cancer cells with stem-cell properties
description	Advanced prostate adenocarcinomas enriched in stem-cell features, as well as variant androgen receptor (AR)-negative neuroendocrine (NE)/small-cell prostate cancers are difficult to treat, and account for up to 30% of prostate cancer-related deaths every year. While existing therapies for prostate cancer such as androgen deprivation therapy (ADT), destroy the bulk of the AR-positive cells within the tumor, eradicating this population eventually leads to castration-resistance, owing to the continued survival of AR-/lo stem-like cells. In this study, we identified a critical nexus between p38MAPK signaling, and the transcription factor Forkhead Box Protein C2 (FOXC2) known to promote cancer stem-cells and metastasis. We demonstrate that prostate cancer cells that are insensitive to ADT, as well as high-grade/NE prostate tumors, are characterized by elevated FOXC2, and that targeting FOXC2 using a well-tolerated p38 inhibitor restores epithelial attributes and ADT-sensitivity, and reduces the shedding of circulating tumor cells in vivo with significant shrinkage in the tumor mass. This study thus specifies a tangible mechanism to target the AR-/lo population of prostate cancer cells with stem-cell properties.
publisher	Nature Publishing Group
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5116559/
_version_	1613734334209982464

Inhibition of FOXC2 restores epithelial phenotype and drug sensitivity in prostate cancer cells with stem-cell properties

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