Article (Scientific journals)
TGFα Promotes Chemoresistance of Malignant Pleural Mesothelioma
Staumont, Bernard; Jamakhani, Majeed; Costa, Chrisostome et al.
2020In Cancers, 12 (6), p. 1484
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Keywords :
mesothelioma; TGFα; chemoresistance; combination therapy
Abstract :
[en] 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.
Disciplines :
Oncology
Author, co-author :
Staumont, Bernard ;  Université de Liège - ULiège > In silico medecine-Biomechanics Research Unit
Jamakhani, Majeed ;  Université de Liège - ULiège > Cancer-Cellular and Molecular Epigenetics
Costa, Chrisostome
Vandermeers, Fabian
Sriramareddy, Sathya Neelature
Redouté, Gaëlle
Mascaux, Céline
Delvenne, Philippe ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
Hubert, Pascale  ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
Safari, Roghaiyeh ;  Université de Liège - ULiège > Cancer-Cellular and Molecular Epigenetics
Willems, Luc  ;  Université de Liège - ULiège > Cancer-Cellular and Molecular Epigenetics
Language :
English
Title :
TGFα Promotes Chemoresistance of Malignant Pleural Mesothelioma
Publication date :
2020
Journal title :
Cancers
eISSN :
2072-6694
Publisher :
Multidisciplinary Digital Publishing Institute (MDPI), Switzerland
Volume :
12
Issue :
6
Pages :
1484
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE]
Télévie [BE]
Fondation contre le Cancer [BE]
ULiège FSR - Université de Liège. Fonds spéciaux pour la recherche [BE]
Fonds Léon Fredericq [BE]
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