A novel role for an RCAN3-derived peptide as a tumor suppressor in breast cancer.
The members of the human regulators of calcineurin (RCAN) protein family are endogenous regulators of the calcineurin (CN)-cytosolic nuclear factor of activated T-cells (NFATc) pathway activation. This function is explained by the presence of a highly conserved calcipressin inhibitor of calcineurin (CIC) motif in RCAN proteins, which has been shown to compete with NFATc for the binding to CN and therefore are able to inhibit NFATc dephosphorylation and activation by CN. Very recently, emerging roles for NFATc proteins in transformation, tumor angiogenesis and metastasis have been described in different cancer cell types. In this work, we report that the overexpression of RCAN3 dramatically inhibits tumor growth and tumor angiogenesis in an orthotopic human breast cancer model. We suggest that RCAN3 exerts these effects in a CN-dependent manner, as mutation of the CIC motif in RCAN3 abolishes the tumor suppressor effect. Moreover, the expression of the EGFP-R3(178-210) peptide, spanning the CIC motif of RCAN3, is able to reproduce all the antitumor effects of RCAN3 full-length protein. Finally, we show that RCAN3 and the EGFP-R3(178-210) peptide inhibit the CN-NFATc signaling pathway and the induction of the NFATc-dependent gene cyclooxygenase-2. Our work suggests that the EGFP-R3(178-210) peptide possess potent tumor suppressor properties and therefore constitutes a novel lead for the development of potent and specific antitumoral agents. Moreover, we propose the targeting of the CN-NFATc pathway in the tumor cells constitutes an effective way to hamper tumor progression by impairing the paracrine network among tumor, endothelial and polymorphonucleated cells.
Cellular Signaling Unit, Human Molecular Genetics Group, Bellvitge Biomedical Research Institute - IDIBELL. L'Hospitalet de Llobregat 08908 Barcelona, Spain.
Sergio
S
Martínez-Høyer
Cellular Signaling Unit, Human Molecular Genetics Group, Bellvitge Biomedical Research Institute - IDIBELL. L'Hospitalet de Llobregat 08908 Barcelona, Spain.
Sònia
S
Solé-Sánchez
Department of Cell Biology, University of Barcelona, Barcelona, Spain.
Fernando
F
Aguado
Departamento de Biología Vascular e Inflamación, Centro Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain.
Sara
S
Martínez-Martínez
Cellular Signaling Unit, Human Molecular Genetics Group, Bellvitge Biomedical Research Institute - IDIBELL. L'Hospitalet de Llobregat 08908 Barcelona, Spain.
Eva
E
Serrano-Candelas
Biomed Division, LEITAT Technological Center, Parc Cientific de Barcelona, Edifici Hèlix, 08028 Barcelona, Spain.
José Luis
JL
Hernández
Department of Pathology, Hospital del Mar (Institut Hospital del Mar d'Investigacions Mèdiques), Autonomous University of Barcelona 08004, Barcelona, Spain.
Mar
M
Iglesias
Departamento de Biología Vascular e Inflamación, Centro Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain.
Juan Miguel
JM
Redondo
Tumor Angiogenesis Group, Translational Research Laboratory, Catalan Institute of Oncology - Bellvitge Biomedical Research Institute - IDIBELL. L'Hospitalet de Llobregat 08908 Barcelona, Spain.
Oriol
O
Casanovas
Biomed Division, LEITAT Technological Center, Parc Cientific de Barcelona, Edifici Hèlix, 08028 Barcelona, Spain.
Ramon
R
Messeguer
Cellular Signaling Unit, Human Molecular Genetics Group, Bellvitge Biomedical Research Institute - IDIBELL. L'Hospitalet de Llobregat 08908 Barcelona, Spain, mpr@idibell.cat.
Mercè
M
Pérez-Riba
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D019703:Calcineurin / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050778:NFATC Transcription Factors; D009389:Neovascularization, Pathologic / Q000235:genetics; D010446:Peptide Fragments / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
D048868:Adaptor Proteins, Signal Transducing; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D010446:Peptide Fragments; C408372:RCAN3 protein, human; D011994:Recombinant Proteins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D019703:Calcineurin