Role of Acid Sphingomyelinase-Induced Signaling in Melanoma Cells for Hematogenous Tumor Metastasis
| Autor: | Matthias Soddemann, Nadine Beckmann, Katrin Anne Becker, Aaron P. Seitz, Alexander Carpinteiro, Iris Helfrich, Erich Gulbins, Barbara Wilker, Bärbel Edelmann, Gabriele Hessler |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Physiology Melanoma Experimental Medizin p38 Mitogen-Activated Protein Kinases p38 kinase lcsh:Physiology Metastasis Ceramide Mice 0302 clinical medicine Medicine lcsh:QD415-436 Neoplasm Metastasis Phosphorylation Extracellular Signal-Regulated MAP Kinases Mice Knockout biology lcsh:QP1-981 Integrin beta1 Melanoma Sphingomyelin Phosphodiesterase 030220 oncology & carcinogenesis Signal transduction Acid sphingomyelinase Signal Transduction medicine.drug Blood Platelets Cell signaling Integrin lcsh:Biochemistry 03 medical and health sciences Cell Line Tumor Cell Adhesion Animals Humans Transplantation Homologous Platelet activation Cell adhesion Protein Kinase Inhibitors Sphingolipids Phospholipase C gamma business.industry medicine.disease Signaling Mice Inbred C57BL Cytoskeletal Proteins 030104 developmental biology Immunology Cancer research biology.protein business Tumor metastasis |
| Zdroj: | Cellular Physiology and Biochemistry, Vol 38, Iss 1, Pp 1-14 (2016) |
| Popis: | Background: Hematogenous metastasis of malignant tumor cells is a multistep process that requires release of tumor cells from the local tumor mass, interaction of the tumor cells with platelets in the blood, and adhesion of either the activated tumor cells or the complexes of platelets and tumor cells to the endothelial cells of the target organ. We have previously shown that the interaction of melanoma cells with platelets results in the release of acid sphingomyelinase (Asm) from activated platelets. Secreted platelet-derived Asm acts on malignant tumor cells to cluster and activate integrins; such clustering and activation are necessary for tumor cell adhesion to endothelial cells and for metastasis. Methods: We examined the response of tumor cells to treatment with extracellular sphingomyelinase or co-incubation with wild-type and Asm-deficient platelets. We determined the phosphorylation and activation of several intracellular signaling molecules, in particular p38 kinase (p38K), phospholipase Cγ (PLCγ), ezrin, and extracellular signal-regulated kinases. Results: Incubation of B16F10 melanoma cells with Asm activates p38 MAP kinase (p38K), phospholipase Cγ (PLCγ), ezrin, and extracellular signal-regulated kinases. Co-incubation of B16F10 melanoma cells with wild-type or Asm-deficient platelets showed that the phosphorylation/activation of p38K is dependent on Asm. Pharmacological blockade of p38K prevents activation of β1 integrin and adhesion in vitro. Most importantly, inhibition of p38K activity in B16F10 melanoma cells prevents tumor cell adhesion and metastasis to the lung in vivo, a finding indicating the importance of p38K for metastasis. Conclusions: Asm, secreted from activated platelets after tumor cell-platelet contact, induces p38K phosphorylation in tumor cells. This in turn stimulates β1 integrin activation that is necessary for adhesion and subsequent metastasis of tumor cells. Thus, inhibition of p38K might be a novel target to prevent tumor metastasis. |
| Databáze: | OpenAIRE |
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