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Histone Deacetylase Inhibitor-Induced Autophagy in Tumor Cells: Implications for p53

Autophagy is an essential process of the eukaryotic cell allowing degradation and recycling of dysfunctional cellular components in response to either physiological or pathological changes. Inhibition of autophagy in combination with chemotherapeutic treatment has emerged as a novel approach in canc...

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Detalles Bibliográficos
Autores principales: Mrakovcic, Maria, Kleinheinz, Johannes, Fröhlich, Leopold F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618532/
https://www.ncbi.nlm.nih.gov/pubmed/30563957
http://dx.doi.org/10.3390/ijms18091883
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author Mrakovcic, Maria
Kleinheinz, Johannes
Fröhlich, Leopold F.
author_facet Mrakovcic, Maria
Kleinheinz, Johannes
Fröhlich, Leopold F.
author_sort Mrakovcic, Maria
collection PubMed
description Autophagy is an essential process of the eukaryotic cell allowing degradation and recycling of dysfunctional cellular components in response to either physiological or pathological changes. Inhibition of autophagy in combination with chemotherapeutic treatment has emerged as a novel approach in cancer treatment leading to cell cycle arrest, differentiation, and apoptosis. Suberoyl hydroxamic acid (SAHA) is a broad-spectrum histone deacetylase inhibitor (HDACi) suppressing family members in multiple HDAC classes. Increasing evidence indicates that SAHA and other HDACi can, in addition to mitochondria-mediated apoptosis, also promote caspase-independent autophagy. SAHA-induced mTOR inactivation as a major regulator of autophagy activating the remaining autophagic core machinery is by far the most reported pathway in several tumor models. However, the question of which upstream mechanisms regulate SAHA-induced mTOR inactivation that consequently initiate autophagy has been mainly left unexplored. To elucidate this issue, we recently initiated a study clarifying different modes of SAHA-induced cell death in two human uterine sarcoma cell lines which led to the conclusion that the tumor suppressor protein p53 could act as a molecular switch between SAHA-triggered autophagic or apoptotic cell death. In this review, we present current research evidence about HDACi-mediated apoptotic and autophagic pathways, in particular with regard to p53 and its therapeutic implications.
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spelling pubmed-56185322017-09-30 Histone Deacetylase Inhibitor-Induced Autophagy in Tumor Cells: Implications for p53 Mrakovcic, Maria Kleinheinz, Johannes Fröhlich, Leopold F. Int J Mol Sci Review Autophagy is an essential process of the eukaryotic cell allowing degradation and recycling of dysfunctional cellular components in response to either physiological or pathological changes. Inhibition of autophagy in combination with chemotherapeutic treatment has emerged as a novel approach in cancer treatment leading to cell cycle arrest, differentiation, and apoptosis. Suberoyl hydroxamic acid (SAHA) is a broad-spectrum histone deacetylase inhibitor (HDACi) suppressing family members in multiple HDAC classes. Increasing evidence indicates that SAHA and other HDACi can, in addition to mitochondria-mediated apoptosis, also promote caspase-independent autophagy. SAHA-induced mTOR inactivation as a major regulator of autophagy activating the remaining autophagic core machinery is by far the most reported pathway in several tumor models. However, the question of which upstream mechanisms regulate SAHA-induced mTOR inactivation that consequently initiate autophagy has been mainly left unexplored. To elucidate this issue, we recently initiated a study clarifying different modes of SAHA-induced cell death in two human uterine sarcoma cell lines which led to the conclusion that the tumor suppressor protein p53 could act as a molecular switch between SAHA-triggered autophagic or apoptotic cell death. In this review, we present current research evidence about HDACi-mediated apoptotic and autophagic pathways, in particular with regard to p53 and its therapeutic implications. MDPI 2017-08-31 /pmc/articles/PMC5618532/ /pubmed/30563957 http://dx.doi.org/10.3390/ijms18091883 Text en © 2017 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 Review
Mrakovcic, Maria
Kleinheinz, Johannes
Fröhlich, Leopold F.
Histone Deacetylase Inhibitor-Induced Autophagy in Tumor Cells: Implications for p53
title Histone Deacetylase Inhibitor-Induced Autophagy in Tumor Cells: Implications for p53
title_full Histone Deacetylase Inhibitor-Induced Autophagy in Tumor Cells: Implications for p53
title_fullStr Histone Deacetylase Inhibitor-Induced Autophagy in Tumor Cells: Implications for p53
title_full_unstemmed Histone Deacetylase Inhibitor-Induced Autophagy in Tumor Cells: Implications for p53
title_short Histone Deacetylase Inhibitor-Induced Autophagy in Tumor Cells: Implications for p53
title_sort histone deacetylase inhibitor-induced autophagy in tumor cells: implications for p53
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618532/
https://www.ncbi.nlm.nih.gov/pubmed/30563957
http://dx.doi.org/10.3390/ijms18091883
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