Interplay between Ret and Fap-1 regulates CD95-mediated apoptosis in medullary thyroid cancer cells
| Autor: | Enrica Favini, Valentina Nicolini, Monica Tortoreto, Franco Zunino, Giuliana Cassinelli, Piera Mondellini, Italia Bongarzone, Patrizia Casalini, Cinzia Lanzi, Nadia Zaffaroni, Giovanna Petrangolini, Giuditta Cuccuru |
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| Rok vydání: | 2011 |
| Předmět: |
endocrine system
congenital hereditary and neonatal diseases and abnormalities Indoles endocrine system diseases Transplantation Heterologous Protein Tyrosine Phosphatase Non-Receptor Type 13 Antineoplastic Agents Apoptosis Mice SCID Dependence receptor Biology Caspase 8 Biochemistry RET Oncoprotein Mice chemistry.chemical_compound Cell Line Tumor medicine Animals Humans Thyroid Neoplasms fas Receptor Phosphorylation neoplasms Pharmacology Cell growth Proto-Oncogene Proteins c-ret Medullary thyroid cancer Tyrosine phosphorylation medicine.disease Fas receptor Carcinoma Neuroendocrine Tumor Burden Cell biology Enzyme Activation Gene Expression Regulation chemistry Carcinoma Medullary NIH 3T3 Cells Cancer research Female Neoplasm Transplantation |
| Zdroj: | Biochemical Pharmacology. 82:778-788 |
| ISSN: | 0006-2952 |
| Popis: | Emerging evidence suggests that Ret oncoproteins expressed in medullary thyroid cancer (MTC) might evade the pro-apoptotic function of the dependence receptor proto-Ret by directly impacting the apoptosis machinery. Identification of the molecular determinants of the interplay between Ret signaling and apoptosis might provide a relevant contribution to the optimization of Ret-targeted therapies. Here, we describe the cross-talk between Ret-M918T oncogenic mutant responsible for type 2B multiple endocrine syndrome (MEN2B), and components of death receptor-mediated extrinsic apoptosis pathway. In the human MEN2B-type MTC cell line MZ-CRC-1 expressing Ret-M918T, Ret was found associated with Fap-1, known as inhibitor of the CD95 death receptor trafficking to the cell membrane, and with procaspase-8, the initiator pro-form caspase in the extrinsic apoptosis pathway. Cell treatment with the anti-tumor Ret kinase inhibitor RPI-1 inhibited tyrosine phosphorylation of procaspase-8, likely inducing its local activation, followed by downregulation of both Ret and Fap-1, and translocation of CD95 into lipid rafts. According to the resulting increase of CD95 cell surface expression, the CD95 agonist antibody CH11 enhanced RPI-1-induced cell growth inhibition and apoptosis. RET RNA interference downregulated Fap-1 protein in MZ-CRC-1 cells, whereas exogenous RET-M918T upregulated Fap-1 in HEK293 cells. Overall, these data indicate that the Ret oncoprotein exerts opposing controls on Fap-1 and CD95, increasing Fap-1 expression and decreasing CD95 cell surface expression. The functional interplay of the Ret mutant with the extrinsic apoptosis pathway provides a mechanism possibly contributing to MTC malignant phenotype and a rational basis for novel therapeutic strategies combining Ret inhibitors and CD95 agonists. |
| Databáze: | OpenAIRE |
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