Fingolimod inhibits proliferation and epithelial–mesenchymal transition in sacral chordoma by inactivating IL-6/STAT3 signalling

Abstract

Purpose: To explore the sensitivity of the immunosuppressive agent fingolimod (FTY720) in chordoma and determine whether it can serve as an appropriate alternate treatment for unresectable tumours in patients after incomplete surgery. Methods: Cell viability assays, colony formation assays and EdU assays were performed to evaluate the sensitivity of chordoma cell lines to FTY720. Transwell invasion assays, wound healing assays, flow cytometry, cell cycle analysis, immunofluorescence analysis, Western blotting analysis and enzyme-linked immunosorbent assays (ELISAs) were performed to evaluate cell invasion, epithelial–mesenchymal transition (EMT) and activation of related pathways after treatment with FTY720. The effect of FTY720 was also evaluated in vivo in a xenograft model. Results: We found that FTY720 inhibited the proliferation, invasion and metastasis of sacral chordoma cells (P < 0.01). FTY720 also inhibited the proliferation of tumour cells in a xenograft model using sacral chordoma cell lines (P < 0.01). The mechanism was related to the EMT and apoptosis of chordoma cells and inactivation of IL-6/STAT3 signalling in vitro and in vivo. Conclusions: Our findings indicate that FTY720 may be an effective therapeutic agent against chordoma. These findings suggest that FTY720 is a novel agent that can treat locally advanced and metastatic chordoma.

COVID-19: Review on latest available drugs and therapies against SARS-CoV-2. Coagulation and inflammation cross-talking

“…Sarilumab, another antibody against IL-6 receptor used in rheumatoid arthritis (Lamb and Deeks, 2018), is being tested in a multicenter, double-blind, clinical phase 2/3 in patients with severe COVID-19 (NCT04315298) (Sanders et al, 2020). Other drugs that showed potential inhibition of IL-6 related JAK/STAT pathway are: Fingolimod which showed to inhibit proliferation and epithelial-mesenchymal transition in sacral chordoma by inactivating IL-6/STAT3 signaling (Wang et al, 2020c), a clinical trial in COVID-19 patients is ongoing (NCT04280588, Phase2) (COVID-19 Clinical Trials, 2020); glatiramer acetate showed potential to downregulate both IL-17 and IL-6 in the central nervous system in an autoimmune encephalitis model (Begum-Haque et al, 2008).…”

“…Sarilumab (Lamb and Deeks, 2018;Sanders et al, 2020) IL-6 Receptor Inhibitor NCT04280588, Phase2 Fingolimod (Wang et al, 2020c;COVID-19 Clinical Trials, 2020) inactivating IL-6/STAT3 pathway NCT04280588, Phase2…”

Targeting Epithelial-to-Mesenchymal Transition in Radioresistance: Crosslinked Mechanisms and Strategies

“…It plays a crucial role in promoting tumor metastasis and EMT process. The S1PR1 antagonist FTY720 can significantly inhibit EMT program by inactivating STAT3 signaling (82,83), further modulating the resistance of cancer cells to therapy. Several studies have shown that S1PR1-mediated sustaining activation of STAT3 is of critical importance in proliferation and multidirectional differentiation of CSCs, which is closely associated with acquired radioresistance in a variety of malignancies such as pancreatic cancer and glioma (28)(29)(30).…”

CMTM3 suppresses chordoma progress through EGFR/STAT3 regulated EMT and TP53 signaling pathway

“…The cells were cultured in serum-free medium overnight before the initiation of the experiments. For migration assay, 1 × 10 5 cells in 0.25 mL of serum-free medium were seeded into the upper chamber [38] and 0.5 mL of medium with 10% FBS was added to the lower chamber and incubated at 37 °C for 24 h. For the invasion assay, 70 μL of 1:10-chilled serum-free mediumdiluted Matrigel (Catalog No. 354234, BD Biosciences, NJ, USA) was precoated in the upper chamber and incubated in a humidified incubator at 37 °C for 60 min.…”