The inhibition of FGF receptor 1 activity mediates sorafenib antiproliferative effects in human malignant pleural mesothelioma tumor-initiating cells

Autor: Elisa Carra, Tullio Florio, Roberto Würth, Rosa Filiberti, Roberto E. Favoni, Antonio Daga, Daniela Marubbi, Federica Barbieri, Luciano Mutti, Alessandra Pattarozzi
Rok vydání: 2017
Předmět:
Mesothelioma
0301 basic medicine
Oncology
Lung Neoplasms
Time Factors
Basic fibroblast growth factor
Fibroblast growth factor
Medicine (miscellaneous)
Apoptosis
Cell Separation
Mice
SCID
chemistry.chemical_compound
0302 clinical medicine
Mice
Inbred NOD
Epidermal growth factor
Medicine
lcsh:QD415-436
Pleural mesothelioma
lcsh:R5-920
Tumor-initiating cells
Sorafenib
ErbB Receptors
030220 oncology & carcinogenesis
Neoplastic Stem Cells
Molecular Medicine
Fibroblast Growth Factor 2
Stem cell
lcsh:Medicine (General)
Signal Transduction
medicine.drug
Niacinamide
medicine.medical_specialty
Cell Survival
Pleural Neoplasms
Down-Regulation
Models
Biological
Biochemistry
Genetics and Molecular Biology (miscellaneous)
lcsh:Biochemistry
03 medical and health sciences
Cancer stem cell
Cell Line
Tumor
Internal medicine
Animals
Humans
Receptor
Fibroblast Growth Factor
Type 1
Viability assay
Autocrine signalling
neoplasms
Protein kinase B
Cell Proliferation
Epidermal Growth Factor
business.industry
Research
Phenylurea Compounds
Mesothelioma
Malignant
Cell Cycle Checkpoints
Cell Biology
030104 developmental biology
chemistry
Cancer research
Myeloid Cell Leukemia Sequence 1 Protein
business
Zdroj: Stem Cell Research & Therapy, Vol 8, Iss 1, Pp 1-17 (2017)
Stem Cell Research & Therapy
ISSN: 1757-6512
DOI: 10.1186/s13287-017-0573-7
Popis: Background Malignant pleural mesothelioma is an aggressive cancer, characterized by rapid progression and high mortality. Persistence of tumor-initiating cells (TICs, or cancer stem cells) after cytotoxic drug treatment is responsible for tumor relapse, and represents one of the main reasons for the poor prognosis of mesothelioma. In fact, identification of the molecules affecting TIC viability is still a significant challenge. Methods TIC-enriched cultures were obtained from 10 human malignant pleural mesotheliomas and cultured in vitro. Three fully characterized tumorigenic cultures, named MM1, MM3, and MM4, were selected and used to assess antiproliferative effects of the multi-kinase inhibitor sorafenib. Cell viability was investigated by MTT assay, and cell cycle analysis as well as induction of apoptosis were determined by flow cytometry. Western blotting was performed to reveal the modulation of protein expression and the phosphorylation status of pathways associated with sorafenib treatment. Results We analyzed the molecular mechanisms of the antiproliferative effects of sorafenib in mesothelioma TIC cultures. Sorafenib inhibited cell cycle progression in all cultures, but only in MM3 and MM4 cells was this effect associated with Mcl-1-dependent apoptosis. To investigate the mechanisms of sorafenib-mediated antiproliferative activity, TICs were treated with epidermal growth factor (EGF) or basic fibroblast growth factor (bFGF) causing, in MM3 and MM4 cells, MEK, ERK1/2, Akt, and STAT3 phosphorylation. These effects were abolished by sorafenib only in bFGF-treated cells, while a modest inhibition occurred after EGF stimulation, suggesting that sorafenib effects are mainly due to FGF receptor (FGFR) inhibition. Indeed, FGFR1 phosphorylation was inhibited by sorafenib. Moreover, in MM1 cells, which release high levels of bFGF and showed autocrine activation of FGFR1 and constitutive phosphorylation/activation of MEK-ERK1/2, sorafenib induced a more effective antiproliferative response, confirming that the main target of the drug is the inhibition of FGFR1 activity. Conclusions These results suggest that, in malignant pleural mesothelioma TICs, bFGF signaling is the main target of the antiproliferative response of sorafenib, acting directly on the FGFR1 activation. Patients with constitutive FGFR1 activation via an autocrine loop may be more sensitive to sorafenib treatment and the analysis of this possibility warrants further clinical investigation. Electronic supplementary material The online version of this article (doi:10.1186/s13287-017-0573-7) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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