Autocrine role for Gas6 with Tyro3 and Axl in leiomyosarcomas.
Leiomyosarcoma (LMS) represent 15 % of adult sarcomas. The aim of this work was to identify novel altered pathways in LMS, which may be of therapeutic value for patients. Thirteen fresh frozen samples of soft tissue and visceral LMS were analyzed and compared with normal smooth muscle uterine tissue (NSM) for phosphoproteomic profile. Four proteins were found differentially expressed including Tyro3. The functional role of Tyro3 and its ligand Gas6 was investigated in two LMS cell lines, SK-LMS-1 and CNIO-AA. Four proteins and phosphoproteins were differentially expressed in LMS samples vs NSM: A loss of FAK Y397 phosphorylation was observed in all LMSs, while Tyro3, MSH2 and PKC theta were consistently overexpressed. Gas6, the major ligand of Tyro3, was expressed in 8 of the 13 LMS samples, and Gas6 expression highly correlated to Akt Y473 phosphorylation and to a lesser extent to Erk1/2 phosphorylation. SK-LMS-1 and CNIO-AA LMS expressed Tyro3, Axl and Gas6 at high level in CNIO-AA while at low levels in SK-LMS-1. Exposure of both cell lines to foretinib, a tyrosine kinase inhibitor of Met, Axl and Tyro3, reduced cell viability and induced caspase 3/7 activation. Transfection of CNIO-AA with small interfering RNA directed against Tyro3 and Axl genes induced a reduction of the expression of the specific proteins and, when combined, significantly reduced CNIO-AA cell viability. Leiomyosarcomas overexpress Tyro3. Gas6, a ligand of Tyro3, exerts an autocrine activities though Tyro3 and Axl in a subgroup of LMS.
Pole des Sciences Cliniques & Centre de Recherche en Cancerologie de Lyon, INSERM UMR5286 Equipe 11, Centre Léon Bérard, Lyon, France.
Hiba
H
el Sayadi
Daniel
D
Pissaloux
Laurent
L
Alberti
Severine
S
Tabone-Eglinger
Dominique
D
Ranchere
Anne Valérie
AV
Decouvelaere
Eric
E
Tabone
Isabelle
I
Ray-Coquard
Christophe
C
Caux
Jérome
J
Fayette
Jean-Yves
JY
Blay
D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000494:pharmacology; D007890:Leiomyosarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D010766:Phosphorylation; D040901:Proteomics; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D014162:Transfection; D014594:Uterine Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
D036341:Intercellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D011994:Recombinant Proteins; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C084944:TYRO3 protein, human; C000722289:AXL protein, human