TGFα Promotes Chemoresistance of Malignant Pleural Mesothelioma
Open Access
- 5 June 2020
- Vol. 12 (6), 1484
- https://doi.org/10.3390/cancers12061484
Abstract
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.Funding Information
- Fonds De La Recherche Scientifique - FNRS (Télévie, CDR)
This publication has 48 references indexed in Scilit:
- Therapeutic antitumor efficacy of anti-epidermal growth factor receptor antibody, cetuximab, against malignant pleural mesotheliomaInternational Journal of Oncology, 2012
- Targeted epidermal growth factor receptor therapy in malignant pleural mesothelioma: Where do we stand?Cancer Treatment Reviews, 2011
- Valproate-doxorubicin: promising therapy for progressing mesothelioma. A phase II studyEuropean Respiratory Journal, 2010
- Synergistic effect of gefitinib and rofecoxib in mesothelioma cellsMolecular Cancer, 2010
- Combined inhibition of MET and EGFR suppresses proliferation of malignant mesothelioma cellsCarcinogenesis: Integrative Cancer Research, 2009
- Antitumor Effects of Doxorubicin Followed by Zoledronic Acid in a Mouse Model of Breast CancerJNCI Journal of the National Cancer Institute, 2008
- Modification of the Primary Tumor Microenvironment by Transforming Growth Factor α-Epidermal Growth Factor Receptor Signaling Promotes Metastasis in an Orthotopic Colon Cancer ModelThe American Journal of Pathology, 2008
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005
- Anti‐tumor mechanisms of valproate: A novel role for an old drugMedicinal Research Reviews, 2002
- Chemotherapy of diffuse malignant mesothelioma. Phase II trials of single-agent 5-fluorouracil and adriamycinCancer, 1984