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Autophagy Pathway Is Required for IL-6 Induced Neuroendocrine Differentiation and Chemoresistance of Prostate Cancer LNCaP Cells

Prostate cancer (PCa) cells undergoing neuroendocrine differentiation (NED) are clinically relevant to the development of relapsed castration-resistant PCa. Increasing evidences show that autophagy involves in the development of neuroendocrine (NE) tumors, including PCa. To clarify the effect of aut...

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Autores principales: Chang, Pei-Ching, Wang, Tao-Yeuan, Chang, Yi-Ting, Chu, Cheng-Ying, Lee, Chin-Ling, Hsu, Hung-Wei, Zhou, Tyng-An, Wu, Zhaoju, Kim, Randie H., Desai, Sonal J., Liu, Shangqin, Kung, Hsing-Jien
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3925144/
https://www.ncbi.nlm.nih.gov/pubmed/24551118
http://dx.doi.org/10.1371/journal.pone.0088556
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author Chang, Pei-Ching
Wang, Tao-Yeuan
Chang, Yi-Ting
Chu, Cheng-Ying
Lee, Chin-Ling
Hsu, Hung-Wei
Zhou, Tyng-An
Wu, Zhaoju
Kim, Randie H.
Desai, Sonal J.
Liu, Shangqin
Kung, Hsing-Jien
author_facet Chang, Pei-Ching
Wang, Tao-Yeuan
Chang, Yi-Ting
Chu, Cheng-Ying
Lee, Chin-Ling
Hsu, Hung-Wei
Zhou, Tyng-An
Wu, Zhaoju
Kim, Randie H.
Desai, Sonal J.
Liu, Shangqin
Kung, Hsing-Jien
author_sort Chang, Pei-Ching
collection PubMed
description Prostate cancer (PCa) cells undergoing neuroendocrine differentiation (NED) are clinically relevant to the development of relapsed castration-resistant PCa. Increasing evidences show that autophagy involves in the development of neuroendocrine (NE) tumors, including PCa. To clarify the effect of autophagy on NED, androgen-sensitive PCa LNCaP cells were examined. Treatment of LNCaP cells with IL-6 resulted in an induction of autophagy. In the absence of androgen, IL-6 caused an even stronger activation of autophagy. Similar result was identified in NED induction. Inhibition of autophagy with chloroquine (CQ) markedly decreased NED. This observation was confirmed by beclin1 and Atg5 silencing experiments. Further supporting the role of autophagy in NED, we found that LC3 was up-regulated in PCa tissue that had relapsed after androgen-deprivation therapy when compared with their primary tumor counterpart. LC3 staining in relapsed PCa tissue showed punctate pattern similar to the staining of chromogranin A (CgA), a marker for NED cells. Moreover, autophagy inhibition induced the apoptosis of IL-6 induced NE differentiated PCa cells. Consistently, inhibition of autophagy by knockdown of beclin1 or Atg5 sensitized NE differentiated LNCaP cells to etoposide, a chemotherapy drug. To identify the mechanisms, phosphorylation of IL-6 downstream targets was analyzed. An increase in phospho-AMPK and a decrease in phospho-mTOR were found, which implies that IL-6 regulates autophagy through the AMPK/mTOR pathway. Most important to this study is the discovery of REST, a neuronal gene-specific transcriptional repressor that is involved in autophagy activation. REST was down-regulated in IL-6 treatment. Knockdown experiments suggest that REST is critical to NED and autophagy activation by IL-6. Together, our studies imply that autophagy is involved in PCa progression and plays a cytoprotective role when NED is induced in PCa cells by IL-6 treatment. These results reveal the potential of targeting autophagy as part of a combined therapeutic regime for NE tumors.
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spelling pubmed-39251442014-02-18 Autophagy Pathway Is Required for IL-6 Induced Neuroendocrine Differentiation and Chemoresistance of Prostate Cancer LNCaP Cells Chang, Pei-Ching Wang, Tao-Yeuan Chang, Yi-Ting Chu, Cheng-Ying Lee, Chin-Ling Hsu, Hung-Wei Zhou, Tyng-An Wu, Zhaoju Kim, Randie H. Desai, Sonal J. Liu, Shangqin Kung, Hsing-Jien PLoS One Research Article Prostate cancer (PCa) cells undergoing neuroendocrine differentiation (NED) are clinically relevant to the development of relapsed castration-resistant PCa. Increasing evidences show that autophagy involves in the development of neuroendocrine (NE) tumors, including PCa. To clarify the effect of autophagy on NED, androgen-sensitive PCa LNCaP cells were examined. Treatment of LNCaP cells with IL-6 resulted in an induction of autophagy. In the absence of androgen, IL-6 caused an even stronger activation of autophagy. Similar result was identified in NED induction. Inhibition of autophagy with chloroquine (CQ) markedly decreased NED. This observation was confirmed by beclin1 and Atg5 silencing experiments. Further supporting the role of autophagy in NED, we found that LC3 was up-regulated in PCa tissue that had relapsed after androgen-deprivation therapy when compared with their primary tumor counterpart. LC3 staining in relapsed PCa tissue showed punctate pattern similar to the staining of chromogranin A (CgA), a marker for NED cells. Moreover, autophagy inhibition induced the apoptosis of IL-6 induced NE differentiated PCa cells. Consistently, inhibition of autophagy by knockdown of beclin1 or Atg5 sensitized NE differentiated LNCaP cells to etoposide, a chemotherapy drug. To identify the mechanisms, phosphorylation of IL-6 downstream targets was analyzed. An increase in phospho-AMPK and a decrease in phospho-mTOR were found, which implies that IL-6 regulates autophagy through the AMPK/mTOR pathway. Most important to this study is the discovery of REST, a neuronal gene-specific transcriptional repressor that is involved in autophagy activation. REST was down-regulated in IL-6 treatment. Knockdown experiments suggest that REST is critical to NED and autophagy activation by IL-6. Together, our studies imply that autophagy is involved in PCa progression and plays a cytoprotective role when NED is induced in PCa cells by IL-6 treatment. These results reveal the potential of targeting autophagy as part of a combined therapeutic regime for NE tumors. Public Library of Science 2014-02-14 /pmc/articles/PMC3925144/ /pubmed/24551118 http://dx.doi.org/10.1371/journal.pone.0088556 Text en © 2014 Chang et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Chang, Pei-Ching
Wang, Tao-Yeuan
Chang, Yi-Ting
Chu, Cheng-Ying
Lee, Chin-Ling
Hsu, Hung-Wei
Zhou, Tyng-An
Wu, Zhaoju
Kim, Randie H.
Desai, Sonal J.
Liu, Shangqin
Kung, Hsing-Jien
Autophagy Pathway Is Required for IL-6 Induced Neuroendocrine Differentiation and Chemoresistance of Prostate Cancer LNCaP Cells
title Autophagy Pathway Is Required for IL-6 Induced Neuroendocrine Differentiation and Chemoresistance of Prostate Cancer LNCaP Cells
title_full Autophagy Pathway Is Required for IL-6 Induced Neuroendocrine Differentiation and Chemoresistance of Prostate Cancer LNCaP Cells
title_fullStr Autophagy Pathway Is Required for IL-6 Induced Neuroendocrine Differentiation and Chemoresistance of Prostate Cancer LNCaP Cells
title_full_unstemmed Autophagy Pathway Is Required for IL-6 Induced Neuroendocrine Differentiation and Chemoresistance of Prostate Cancer LNCaP Cells
title_short Autophagy Pathway Is Required for IL-6 Induced Neuroendocrine Differentiation and Chemoresistance of Prostate Cancer LNCaP Cells
title_sort autophagy pathway is required for il-6 induced neuroendocrine differentiation and chemoresistance of prostate cancer lncap cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3925144/
https://www.ncbi.nlm.nih.gov/pubmed/24551118
http://dx.doi.org/10.1371/journal.pone.0088556
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