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Article

TGFα Promotes Chemoresistance of Malignant Pleural Mesothelioma

1
Molecular and Cellular Epigenetics (GIGA) and Molecular Biology (GxABT), University of Liège, 4000 Liège, Belgium
2
Department of Pulmonology, Strasbourg University Hospital, 67091 Strasbourg, France
3
Interface de Recherche Fondamentale et Appliquée en Cancérologie, INSERM U1113, Université de Strasbourg, 67200 Strasbourg, France
4
Laboratory of Experimental Pathology, GIGA-Cancer, University of Liège, 4000 Liège, Belgium
*
Author to whom correspondence should be addressed.
Equally contributing authors.
Cancers 2020, 12(6), 1484; https://doi.org/10.3390/cancers12061484
Received: 13 May 2020 / Revised: 1 June 2020 / Accepted: 3 June 2020 / Published: 6 June 2020
(This article belongs to the Section Molecular Cancer Biology)
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. View Full-Text
Keywords: mesothelioma; TGFα; chemoresistance; combination therapy mesothelioma; TGFα; chemoresistance; combination therapy
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MDPI and ACS Style

Staumont, B.; Jamakhani, M.; Costa, C.; Vandermeers, F.; Sriramareddy, S.N.; Redouté, G.; Mascaux, C.; Delvenne, P.; Hubert, P.; Safari, R.; Willems, L. TGFα Promotes Chemoresistance of Malignant Pleural Mesothelioma. Cancers 2020, 12, 1484. https://doi.org/10.3390/cancers12061484

AMA Style

Staumont B, Jamakhani M, Costa C, Vandermeers F, Sriramareddy SN, Redouté G, Mascaux C, Delvenne P, Hubert P, Safari R, Willems L. TGFα Promotes Chemoresistance of Malignant Pleural Mesothelioma. Cancers. 2020; 12(6):1484. https://doi.org/10.3390/cancers12061484

Chicago/Turabian Style

Staumont, Bernard, Majeed Jamakhani, Chrisostome Costa, Fabian Vandermeers, Sathya Neelature Sriramareddy, Gaëlle Redouté, Céline Mascaux, Philippe Delvenne, Pascale Hubert, Roghaiyeh Safari, and Luc Willems. 2020. "TGFα Promotes Chemoresistance of Malignant Pleural Mesothelioma" Cancers 12, no. 6: 1484. https://doi.org/10.3390/cancers12061484

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