title: Fingolimod inhibits PDGF-B-induced migration of vascular smooth muscle cell by down-regulating the S1PR1/S1PR3 pathway.
abstract: Platelet Derived Growth Factor (PDGF) and sphingosine-1-phosphate (S1P) pathways play a key role in mural cell recruitment during tumor growth and angiogenesis. Fingolimod, a S1P analogue, has been shown to exert antitumor and antiangiogenic properties. However, molecular targets and modes of action of fingolimod remain unclear. In this study, we confirmed the antagonizing action of S1P and PDGF-B on rat vascular smooth muscle cell (VSMCs) growth and migration. We then compared siRNA and/or fingolimod (100 nM) treatments on PDGFR-β, S1PR1 S1PR2 and S1PR3 expression. Fingolimod induced a 50% reduction in S1PR3 protein expression which was cumulative with that obtained with anti-S1PR3 siRNA. We found that siRNA-induced inhibition of both PDGFR-β and S1PR3 was the most effective means to block VSMC migration induced by PDGF-B. Finally, we observed that fingolimod treatment associated with anti-S1PR1 siRNA principally inhibited VSMC growth while in combination with anti-S1PR3 siRNA it strongly inhibited VSMC migration. These results suggest that for rat VSMCs, the PDGFR-S1PR1 pathway is predominantly dedicated to cell growth while PDGFR-S1PR3 stimulates cell migration. As an S1P analogue, fingolimod is considered a potent activator of S1PR1 and S1PR3. However, its action on the PDGFR-S1PR platform appears to be dependent on S1PR1 and S1PR3 specific downregulation. Considering that the S1P pathway has already been shown to exert various crosstalks with tyrosine kinase pathways, it seems of great interest to evaluate fingolimod potential in combination with the numerous tyrosine kinase inhibitors used in oncology.
authors: Department of Biochemistry and Molecular Genetic, CHU Dupuytren, Limoges, France.
authors: Yoanne
authors: Y
authors: Mousseau
authors: Séverine
authors: S
authors: Mollard
authors: Laurence
authors: L
authors: Richard
authors: Angélique
authors: A
authors: Nizou
authors: Karine
authors: K
authors: Faucher-Durand
authors: Jeanne
authors: J
authors: Cook-Moreau
authors: Hao
authors: H
authors: Qiu
authors: Yasser
authors: Y
authors: Baaj
authors: Benoit
authors: B
authors: Funalot
authors: Laurent
authors: L
authors: Fourcade
authors: Franck G
authors: FG
authors: Sturtz
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D000068876:Fingolimod Hydrochloride; D007150:Immunohistochemistry; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D011409:Propylene Glycols / Q000494:pharmacology*; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology*; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000081025:Sphingosine-1-Phosphate Receptors
chemical_list: D011409:Propylene Glycols; D020574:Proto-Oncogene Proteins c-sis; D049349:Receptors, Lysosphingolipid; C578616:S1PR1 protein, rat; C578617:S1PR3 protein, rat; D000081025:Sphingosine-1-Phosphate Receptors; D020797:Receptor, Platelet-Derived Growth Factor beta; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine