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Dual role of autophagy on docetaxel-sensitivity in prostate cancer cells

Prostate cancer (PC) is one of the leading causes of death in males. Available treatments often lead to the appearance of chemoresistant foci and metastases, with mechanisms still partially unknown. Within tumour mass, autophagy may promote cell survival by enhancing cancer cells tolerability to dif...

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Autores principales: Cristofani, Riccardo, Montagnani Marelli, Marina, Cicardi, Maria Elena, Fontana, Fabrizio, Marzagalli, Monica, Limonta, Patrizia, Poletti, Angelo, Moretti, Roberta Manuela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117300/
https://www.ncbi.nlm.nih.gov/pubmed/30166521
http://dx.doi.org/10.1038/s41419-018-0866-5
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author Cristofani, Riccardo
Montagnani Marelli, Marina
Cicardi, Maria Elena
Fontana, Fabrizio
Marzagalli, Monica
Limonta, Patrizia
Poletti, Angelo
Moretti, Roberta Manuela
author_facet Cristofani, Riccardo
Montagnani Marelli, Marina
Cicardi, Maria Elena
Fontana, Fabrizio
Marzagalli, Monica
Limonta, Patrizia
Poletti, Angelo
Moretti, Roberta Manuela
author_sort Cristofani, Riccardo
collection PubMed
description Prostate cancer (PC) is one of the leading causes of death in males. Available treatments often lead to the appearance of chemoresistant foci and metastases, with mechanisms still partially unknown. Within tumour mass, autophagy may promote cell survival by enhancing cancer cells tolerability to different cell stresses, like hypoxia, starvation or those triggered by chemotherapic agents. Because of its connection with the apoptotic pathways, autophagy has been differentially implicated, either as prodeath or prosurvival factor, in the appearance of more aggressive tumours. Here, in three PC cells (LNCaP, PC3, and DU145), we tested how different autophagy inducers modulate docetaxel-induced apoptosis. We selected the mTOR-independent disaccharide trehalose and the mTOR-dependent macrolide lactone rapamycin autophagy inducers. In castration-resistant PC (CRPC) PC3 cells, trehalose specifically prevented intrinsic apoptosis in docetaxel-treated cells. Trehalose reduced the release of cytochrome c triggered by docetaxel and the formation of aberrant mitochondria, possibly by enhancing the turnover of damaged mitochondria via autophagy (mitophagy). In fact, trehalose increased LC3 and p62 expression, LC3-II and p62 (p62 bodies) accumulation and the induction of LC3 puncta. In docetaxel-treated cells, trehalose, but not rapamycin, determined a perinuclear mitochondrial aggregation (mito-aggresomes), and mitochondria specifically colocalized with LC3 and p62-positive autophagosomes. In PC3 cells, rapamycin retained its ability to activate autophagy without evidences of mitophagy even in presence of docetaxel. Interestingly, these results were replicated in LNCaP cells, whereas trehalose and rapamycin did not modify the response to docetaxel in the ATG5-deficient (autophagy resistant) DU145 cells. Therefore, autophagy is involved to alter the response to chemotherapy in combination therapies and the response may be influenced by the different autophagic pathways utilized and by the type of cancer cells.
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spelling pubmed-61173002018-08-31 Dual role of autophagy on docetaxel-sensitivity in prostate cancer cells Cristofani, Riccardo Montagnani Marelli, Marina Cicardi, Maria Elena Fontana, Fabrizio Marzagalli, Monica Limonta, Patrizia Poletti, Angelo Moretti, Roberta Manuela Cell Death Dis Article Prostate cancer (PC) is one of the leading causes of death in males. Available treatments often lead to the appearance of chemoresistant foci and metastases, with mechanisms still partially unknown. Within tumour mass, autophagy may promote cell survival by enhancing cancer cells tolerability to different cell stresses, like hypoxia, starvation or those triggered by chemotherapic agents. Because of its connection with the apoptotic pathways, autophagy has been differentially implicated, either as prodeath or prosurvival factor, in the appearance of more aggressive tumours. Here, in three PC cells (LNCaP, PC3, and DU145), we tested how different autophagy inducers modulate docetaxel-induced apoptosis. We selected the mTOR-independent disaccharide trehalose and the mTOR-dependent macrolide lactone rapamycin autophagy inducers. In castration-resistant PC (CRPC) PC3 cells, trehalose specifically prevented intrinsic apoptosis in docetaxel-treated cells. Trehalose reduced the release of cytochrome c triggered by docetaxel and the formation of aberrant mitochondria, possibly by enhancing the turnover of damaged mitochondria via autophagy (mitophagy). In fact, trehalose increased LC3 and p62 expression, LC3-II and p62 (p62 bodies) accumulation and the induction of LC3 puncta. In docetaxel-treated cells, trehalose, but not rapamycin, determined a perinuclear mitochondrial aggregation (mito-aggresomes), and mitochondria specifically colocalized with LC3 and p62-positive autophagosomes. In PC3 cells, rapamycin retained its ability to activate autophagy without evidences of mitophagy even in presence of docetaxel. Interestingly, these results were replicated in LNCaP cells, whereas trehalose and rapamycin did not modify the response to docetaxel in the ATG5-deficient (autophagy resistant) DU145 cells. Therefore, autophagy is involved to alter the response to chemotherapy in combination therapies and the response may be influenced by the different autophagic pathways utilized and by the type of cancer cells. Nature Publishing Group UK 2018-08-30 /pmc/articles/PMC6117300/ /pubmed/30166521 http://dx.doi.org/10.1038/s41419-018-0866-5 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Cristofani, Riccardo
Montagnani Marelli, Marina
Cicardi, Maria Elena
Fontana, Fabrizio
Marzagalli, Monica
Limonta, Patrizia
Poletti, Angelo
Moretti, Roberta Manuela
Dual role of autophagy on docetaxel-sensitivity in prostate cancer cells
title Dual role of autophagy on docetaxel-sensitivity in prostate cancer cells
title_full Dual role of autophagy on docetaxel-sensitivity in prostate cancer cells
title_fullStr Dual role of autophagy on docetaxel-sensitivity in prostate cancer cells
title_full_unstemmed Dual role of autophagy on docetaxel-sensitivity in prostate cancer cells
title_short Dual role of autophagy on docetaxel-sensitivity in prostate cancer cells
title_sort dual role of autophagy on docetaxel-sensitivity in prostate cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117300/
https://www.ncbi.nlm.nih.gov/pubmed/30166521
http://dx.doi.org/10.1038/s41419-018-0866-5
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