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

Pattarozzi, A; Carra, E; Favoni, RE; Würth, R; Marubbi, D; Filiberti, R; Mutti, L; Florio, T; Barbieri, F; Daga, A

Abstract

Tumor-initiating cells (TICs), the subset of cells within tumors endowed with stem-like features, being highly resistant to conventional cytotoxic drugs, are the major cause of tumor relapse. The identification of molecules able to target TICs remains a significant challenge in cancer therapy. Using TIC-enriched cultures (MM1, MM3 and MM4), from 3 human malignant pleural mesotheliomas (MPM), we tested the effects of sorafenib on cell survival and the intracellular mechanisms involved. Sorafenib inhibited cell-cycle progression in all the TIC cultures, but only in MM3 and MM4 cells this effect was associated with induction of apoptosis via the down-regulation of Mcl-1. Although sorafenib inhibits the activity of several tyrosine kinases, its effects are mainly ascribed to Raf inhibition. To investigate the mechanisms of sorafenib-mediated antiproliferative activity, TICs were treated with EGF or bFGF causing, in MM3 and MM4 cells, MEK, ERK1/2, Akt and STAT3 phosphorylation. These effects were significantly reduced by sorafenib in bFGF-treated cells, while a slight inhibition occurred after EGF stimulation, suggesting that sorafenib effects are mainly due to FGFR inhibition. Indeed, FGFR1 phosphorylation was inhibited by sorafenib.
A different picture was observed in MM1 cells, which, releasing high levels of bFGF, showed an autocrine activation of FGFR1 and a constitutive phosphorylation/activation of MEK-ERK1/2. A powerful inhibitory response to sorafenib was observed in these cells, indirectly confirming the central role of sorafenib as FGFR inhibitor.
These results suggest that bFGF signaling may impact antiproliferative response to sorafenib of MPM TICs, which is mainly mediated by a direct FGFR targeting.

Citation

Pattarozzi, A., Carra, E., Favoni, R., Würth, R., Marubbi, D., Filiberti, R., …Daga, A. (2017). The inhibition of FGF receptor 1 activity mediates sorafenib-induced antiproliferative effects in human mesothelioma tumor-initiating cells. Stem Cell Research and Therapy, 8(119), https://doi.org/10.1186/s13287-017-0573-7

• Journal Article Type: Article
• Acceptance Date: Apr 4, 2017
• Online Publication Date: May 25, 2017
• Publication Date: May 25, 2017
• Deposit Date: May 9, 2017
• Publicly Available Date: May 31, 2017
• Journal: Stem Cell Research & Therapy
• Electronic ISSN: 1757-6512
• Publisher: Springer Verlag
• Volume: 8
• Issue: 119
• DOI: https://doi.org/10.1186/s13287-017-0573-7
• Publisher URL: http://dx.doi.org/10.1186/s13287-017-0573-7
• Related Public URLs: http://stemcellres.biomedcentral.com/