The actin cytoskeleton-associated protein zyxin acts as a tumor suppressor in Ewing tumor cells.
Changes in cell architecture, essentially linked to profound cytoskeleton rearrangements, are common features accompanying cell transformation. Supporting the involvement of the microfilament network in tumor cell behavior, several actin-binding proteins, including zyxin, a potential regulator of actin polymerization, may play a role in oncogenesis. In this work, we investigate the status of zyxin in Ewing tumors, a family of pediatric malignancies of bone and soft tissues, which are mainly associated with a t(11;22) chromosomal translocation encoding the EWS-FLI1 oncoprotein. We observe that EWS-FLI1-transformed murine fibroblasts, as well as human Ewing tumor-derived SK-N-MC cells, exhibit a complete disruption of their actin cytoskeleton, retaining very few stress fibers, focal adhesions and cell-to-cell contacts. We show that within these cells, zyxin is expressed at very low levels and remains diffusely distributed throughout the cytoplasm, instead of concentrating in actin-rich dynamic structures. We demonstrate that zyxin gene transfer into EWS-FLI1-transformed fibroblasts elicits reconstitution of zyxin-rich focal adhesions and intercellular junctions, dramatic reorganization of the actin cytoskeleton, decreased cell motility, inhibition of anchorage-independent growth and impairment of tumor formation in athymic mice. We observe similar phenotypic changes after zyxin gene transfer in SK-N-MC cells, suggesting that zyxin has tumor suppressor activity in Ewing tumor cells.
Amsellem
Valérie
V
Laboratoire de Biotechnologie et Pharmacologie génétique appliquée, CNRS UMR 8113, Ecole Normale Supérieure de Cachan, 61 avenue du Président Wilson, 94230 Cachan, France. vamsel@igr.fr
Kryszke
Marie-Hélène
MH
Hervy
Martial
M
Subra
Frédéric
F
Athman
Rafika
R
Leh
Hervé
H
Brachet-Ducos
Corinne
C
Auclair
Christian
C
D008841:Actin Cytoskeleton / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins; D022001:Focal Adhesions / Q000378:metabolism; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D034802:RNA-Binding Protein EWS / Q000235:genetics; D012512:Sarcoma, Ewing / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014162:Transfection; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D060589:Zyxin
D003598:Cytoskeletal Proteins; D006023:Glycoproteins; D034802:RNA-Binding Protein EWS; D025521:Tumor Suppressor Proteins; C092842:ZYX protein, human; D060589:Zyxin