title: EMT phenotype is induced by increased Src kinase activity via Src-mediated caspase-8 phosphorylation.
abstract: Caspase-8 governs multiple cell responses to the microenvironmental cues. However, its integration of "death-life" signalings remains elusive. In our study, the role of caspase-8-Src is well-established as a promoter for migration or metastasis in Casp8(+)Src(+) A549/H226 cells in vivo and in vitro. In particular for nude mice models, mice implanted with Casp8(+)Src(+) A459/H226 cells remarkably increased spontaneous tumor metastatic burden with a significant survival disadvantage. Additionally, we detect that Src-mediated caspase-8 phosphorylation stimulates Src phosphorylation at Tyr-416 via the linkage of Src SH2 domain with phosph-Tyr-380 site of caspase-8. In turn, activated Src can efficiently induce epithelial-mesenchymal transition (EMT) phenotypic features to promote tumor cells metastasis. Surprisingly, RXDLL motif deletion in the DEDa of caspase-8 attenuates tumor cell migration or metastasis via impairing the recruitment of caspase-8 into the cellular periphery where activated Src is subject to caspase-8 phosphorylation. Together, a simple model is that the peripherization of caspase-8 is well-poised to facilitate Src-mediated caspase-8 phosphrylation at Tyr-380, then binding of phospho-Tyr380 of caspase-8 to Src SH2 domain may maintain Src in an active conformation to induce EMT phenotype, a key step toward cancer metastasis.
authors.affiliation: Department of Oncosurgery, First Affiliated Hospital of Medical College of Xi'an Jiao Tong University, Xi'an, Shaanxi Province.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.forename: XiaoJun
authors.initials: X
authors.lastname: Li
authors.forename: XiangFei
authors.initials: X
authors.lastname: Sun
authors.forename: YunFeng
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hong
authors.initials: H
authors.lastname: Ren
mesh_terms: D000818:Animals; D001665:Binding Sites; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D054443:Cell Migration Assays; D004789:Enzyme Activation; D058750:Epithelial-Mesenchymal Transition; D005455:Fluorescent Antibody Technique; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D039564:Integrin alphaV / Q000235:genetics / Q000378:metabolism; D039663:Integrin beta4 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D014443:Tyrosine / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D018909:src Homology Domains; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D039564:Integrin alphaV; D039663:Integrin beta4; D014443:Tyrosine; D019061:src-Family Kinases; C505530:CASP8 protein, human; D053181:Caspase 8