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TGFα Promotes Chemoresistance of Malignant Pleural Mesothelioma
Background: There is no standard chemotherapy for refractory or relapsing malignant pleural mesothelioma (MPM). Our previous reports nevertheless indicated that a combination of an anthracycline (doxorubicin) and a lysine deacetylase inhibitor (valproic acid, VPA) synergize to induce the apoptosis o...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352199/ https://www.ncbi.nlm.nih.gov/pubmed/32517259 http://dx.doi.org/10.3390/cancers12061484 |
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author | Staumont, Bernard Jamakhani, Majeed Costa, Chrisostome Vandermeers, Fabian Sriramareddy, Sathya Neelature Redouté, Gaëlle Mascaux, Céline Delvenne, Philippe Hubert, Pascale Safari, Roghaiyeh Willems, Luc |
author_facet | Staumont, Bernard Jamakhani, Majeed Costa, Chrisostome Vandermeers, Fabian Sriramareddy, Sathya Neelature Redouté, Gaëlle Mascaux, Céline Delvenne, Philippe Hubert, Pascale Safari, Roghaiyeh Willems, Luc |
author_sort | Staumont, Bernard |
collection | PubMed |
description | Background: There is no standard chemotherapy for refractory or relapsing malignant pleural mesothelioma (MPM). Our previous reports nevertheless indicated that a combination of an anthracycline (doxorubicin) and a lysine deacetylase inhibitor (valproic acid, VPA) synergize to induce the apoptosis of MPM cells and reduce tumor growth in mouse models. A Phase I/II clinical trial indicated that this regimen is a promising therapeutic option for a proportion of MPM patients. Methods: The transcriptomes of mesothelioma cells were compared after Illumina HiSeq 4000 sequencing. The expression of differentially expressed genes was inhibited by RNA interference. Apoptosis was determined by cell cycle analysis and Annexin V/7-AAD labeling. Protein expression was assessed by immunoblotting. Preclinical efficacy was evaluated in BALB/c and NOD-SCID mice. Results: To understand the mechanisms involved in chemoresistance, the transcriptomes of two MPM cell lines displaying different responses to VPA-doxorubicin were compared. Among the differentially expressed genes, transforming growth factor alpha (TGFα) was associated with resistance to this regimen. The silencing of TGFα by RNA interference correlated with a significant increase in apoptosis, whereas the overexpression of TGFα desensitized MPM cells to the apoptosis induced by VPA and doxorubicin. The multi-targeted inhibition of histone deacetylase (HDAC), HER2 and TGFα receptor (epidermal growth factor receptor/EGFR) improved treatment efficacy in vitro and reduced tumor growth in two MPM mouse models. Finally, TGFα expression but not EGFR correlated with patient survival. Conclusions: Our data show that TGFα but not its receptor EGFR is a key factor in resistance to MPM chemotherapy. This observation may contribute to casting light on the promising but still controversial role of EGFR signaling in MPM therapy. |
format | Online Article Text |
id | pubmed-7352199 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-73521992020-07-15 TGFα Promotes Chemoresistance of Malignant Pleural Mesothelioma Staumont, Bernard Jamakhani, Majeed Costa, Chrisostome Vandermeers, Fabian Sriramareddy, Sathya Neelature Redouté, Gaëlle Mascaux, Céline Delvenne, Philippe Hubert, Pascale Safari, Roghaiyeh Willems, Luc Cancers (Basel) Article Background: There is no standard chemotherapy for refractory or relapsing malignant pleural mesothelioma (MPM). Our previous reports nevertheless indicated that a combination of an anthracycline (doxorubicin) and a lysine deacetylase inhibitor (valproic acid, VPA) synergize to induce the apoptosis of MPM cells and reduce tumor growth in mouse models. A Phase I/II clinical trial indicated that this regimen is a promising therapeutic option for a proportion of MPM patients. Methods: The transcriptomes of mesothelioma cells were compared after Illumina HiSeq 4000 sequencing. The expression of differentially expressed genes was inhibited by RNA interference. Apoptosis was determined by cell cycle analysis and Annexin V/7-AAD labeling. Protein expression was assessed by immunoblotting. Preclinical efficacy was evaluated in BALB/c and NOD-SCID mice. Results: To understand the mechanisms involved in chemoresistance, the transcriptomes of two MPM cell lines displaying different responses to VPA-doxorubicin were compared. Among the differentially expressed genes, transforming growth factor alpha (TGFα) was associated with resistance to this regimen. The silencing of TGFα by RNA interference correlated with a significant increase in apoptosis, whereas the overexpression of TGFα desensitized MPM cells to the apoptosis induced by VPA and doxorubicin. The multi-targeted inhibition of histone deacetylase (HDAC), HER2 and TGFα receptor (epidermal growth factor receptor/EGFR) improved treatment efficacy in vitro and reduced tumor growth in two MPM mouse models. Finally, TGFα expression but not EGFR correlated with patient survival. Conclusions: Our data show that TGFα but not its receptor EGFR is a key factor in resistance to MPM chemotherapy. This observation may contribute to casting light on the promising but still controversial role of EGFR signaling in MPM therapy. MDPI 2020-06-06 /pmc/articles/PMC7352199/ /pubmed/32517259 http://dx.doi.org/10.3390/cancers12061484 Text en © 2020 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 Staumont, Bernard Jamakhani, Majeed Costa, Chrisostome Vandermeers, Fabian Sriramareddy, Sathya Neelature Redouté, Gaëlle Mascaux, Céline Delvenne, Philippe Hubert, Pascale Safari, Roghaiyeh Willems, Luc TGFα Promotes Chemoresistance of Malignant Pleural Mesothelioma |
title | TGFα Promotes Chemoresistance of Malignant Pleural Mesothelioma |
title_full | TGFα Promotes Chemoresistance of Malignant Pleural Mesothelioma |
title_fullStr | TGFα Promotes Chemoresistance of Malignant Pleural Mesothelioma |
title_full_unstemmed | TGFα Promotes Chemoresistance of Malignant Pleural Mesothelioma |
title_short | TGFα Promotes Chemoresistance of Malignant Pleural Mesothelioma |
title_sort | tgfα promotes chemoresistance of malignant pleural mesothelioma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352199/ https://www.ncbi.nlm.nih.gov/pubmed/32517259 http://dx.doi.org/10.3390/cancers12061484 |
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