Interplay between Ret and Fap-1 regulates CD95-mediated apoptosis in medullary thyroid cancer cells

Valentina Nicolini, Giuliana Cassinelli, Giuditta Cuccuru, Italia Bongarzone, Giovanna Petrangolini, Monica Tortoreto, Piera Mondellini, Patrizia Casalini, Enrica Favini, Nadia Zaffaroni, Franco Zunino, Cinzia Lanzi

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Abstract

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.

Original languageEnglish
Pages (from-to)778-788
Number of pages11
JournalBiochemical Pharmacology
Volume82
Issue number7
DOIs
Publication statusPublished - Oct 1 2011

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Keywords

  • Caspase 8
  • CD95
  • Fap-1
  • Medullary thyroid cancer
  • MEN2B
  • RET oncogene

ASJC Scopus subject areas

  • Pharmacology
  • Biochemistry

Cite this

Nicolini, V., Cassinelli, G., Cuccuru, G., Bongarzone, I., Petrangolini, G., Tortoreto, M., Mondellini, P., Casalini, P., Favini, E., Zaffaroni, N., Zunino, F., & Lanzi, C. (2011). Interplay between Ret and Fap-1 regulates CD95-mediated apoptosis in medullary thyroid cancer cells. Biochemical Pharmacology, 82(7), 778-788. https://doi.org/10.1016/j.bcp.2011.06.037