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The doxorubicin-induced cell motility network is under the control of the ceramide-activated protein phosphatase 1 alpha.
Canals, Daniel; Salamone, Silvia; Santacreu, Bruno Jaime; Aguilar, Daniel; Hernandez-Corbacho, María José; Ostermeyer-Fay, Anne G; Greene, Meaghan; Nemeth, Erika; Haley, John D; Obeid, Lina M; Hannun, Yusuf A.
Afiliación
  • Canals D; Department of Medicine, Stony Brook University, Stony Brook, NY, USA.
  • Salamone S; Department of Medicine, Stony Brook University, Stony Brook, NY, USA.
  • Santacreu BJ; Department of Medicine, Stony Brook University, Stony Brook, NY, USA.
  • Aguilar D; Facultad de Farmacia y Bioquimica, Catedra de Biologia Celular y Molecular, Buenos Aires, Argentina.
  • Hernandez-Corbacho MJ; Biomedical Research Networking Center in Hepatic and Digestive Diseases (CIBEREHD), Barcelona, Spain.
  • Ostermeyer-Fay AG; Department of Medicine, Stony Brook University, Stony Brook, NY, USA.
  • Greene M; Department of Medicine, Stony Brook University, Stony Brook, NY, USA.
  • Nemeth E; Department of Medicine, Stony Brook University, Stony Brook, NY, USA.
  • Haley JD; Department of Medicine, Stony Brook University, Stony Brook, NY, USA.
  • Obeid LM; Department of Medicine, Stony Brook University, Stony Brook, NY, USA.
  • Hannun YA; Department of Pathology, Stony Brook University, Stony Brook, NY, USA.
FASEB J ; 35(3): e21396, 2021 03.
Article en En | MEDLINE | ID: mdl-33583073
ABSTRACT
We have recently reported that a specific pool of ceramide, located in the plasma membrane, mediated the effects of sublethal doses of the chemotherapeutic compound doxorubicin on enhancing cancer cell migration. We identified neutral sphingomyelinase 2 (nSMase2) as the enzyme responsible to generate this bioactive pool of ceramide. In this work, we explored the role of members of the protein phosphatases 1 family (PP1), and we identified protein phosphatase 1 alpha isoform (PP1 alpha) as the specific PP1 isoform to mediate this phenotype. Using a bioinformatics approach, we build a functional interaction network based on phosphoproteomics data on plasma membrane ceramide. This led to the identification of several ceramide-PP1 alpha downstream substrates. Studies on phospho mutants of ezrin (T567) and Scrib (S1378/S1508) demonstrated that their dephosphorylation is sufficient to enhance cell migration. In summary, we identified a mechanism where reduced doses of doxorubicin result in the dysregulation of cytoskeletal proteins and enhanced cell migration. This mechanism could explain the reported effects of doxorubicin worsening cancer metastasis in animal models.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Doxorrubicina / Ceramidas / Proteína Fosfatasa 1 Límite: Humans Idioma: En Revista: FASEB J Asunto de la revista: BIOLOGIA / FISIOLOGIA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Doxorrubicina / Ceramidas / Proteína Fosfatasa 1 Límite: Humans Idioma: En Revista: FASEB J Asunto de la revista: BIOLOGIA / FISIOLOGIA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos
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