title: RAC1b overexpression stimulates proliferation and NF-kB-mediated anti-apoptotic signaling in thyroid cancer cells.
abstract: Overexpression of tumor-associated RAC1b has been recently highlighted as one of the most promising targets for therapeutic intervention in colon, breast, lung and pancreatic cancer. RAC1b is a hyperactive variant of the small GTPase RAC1 and has been recently shown to be overexpressed in a subset of papillary thyroid carcinomas associated with unfavorable outcome. Using the K1 PTC derived cell line as an in vitro model, we observed that both RAC1 and RAC1b were able to induce a significant increase on NF-kB and cyclin D1 reporter activity. A clear p65 nuclear localization was found in cells transfected with RAC1b-WT, confirming NF-kB canonical pathway activation. Consistently, we observed a RAC1b-mediated decrease in IκBα (NF-kB inhibitor) protein levels. Moreover, we show that RAC1b overexpression stimulates G1/S progression and protects thyroid cells against induced apoptosis, the latter through a process involving the NF-kB pathway. Present data support previous findings suggesting an important role for RAC1b in the development of follicular cell-derived thyroid malignancies and point out NF-kB activation as one of the molecular mechanisms associated with the pro-tumorigenic advantage of RAC1b overexpression in thyroid carcinomas.
authors.affiliation: Unidade de Investigação de Patobiologia Molecular, Instituto Português de Oncologia de Lisboa Francisco Gentil E.P.E., Lisboa, Portugal.
authors.forename: Márcia
authors.initials: M
authors.lastname: Faria
authors.affiliation: BioISI-Biosystems and Integrative Sciences Institute, Faculdade de Ciências da Universidade de Lisboa, Portugal.|Instituto Nacional de Saúde, Doutor. Ricardo Jorge, Lisboa, Portugal.
authors.forename: Paulo
authors.initials: P
authors.lastname: Matos
authors.affiliation: Serviço de Anatomia Patológica, Instituto Português de Oncologia de Lisboa Francisco Gentil E.P.E., Lisboa, Portugal.
authors.forename: Teresa
authors.initials: T
authors.lastname: Pereira
authors.affiliation: Serviço de Anatomia Patológica, Instituto Português de Oncologia de Lisboa Francisco Gentil E.P.E., Lisboa, Portugal.
authors.forename: Rafael
authors.initials: R
authors.lastname: Cabrera
authors.affiliation: Unidade de Investigação de Patobiologia Molecular, Instituto Português de Oncologia de Lisboa Francisco Gentil E.P.E., Lisboa, Portugal.
authors.forename: Bruno A
authors.initials: BA
authors.lastname: Cardoso
authors.affiliation: Serviço de Endocrinologia, Diabetes e Metabolismo, do CHLN-Hospital Santa Maria, Lisboa, Portugal.|ISAMB-Instituto de Saúde Ambiental, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Bugalho
authors.affiliation: Unidade de Investigação de Patobiologia Molecular, Instituto Português de Oncologia de Lisboa Francisco Gentil E.P.E., Lisboa, Portugal.|Serviço de Endocrinologia, Diabetes e Metabolismo, do CHLN-Hospital Santa Maria, Lisboa, Portugal.|ISAMB-Instituto de Saúde Ambiental, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Ana Luísa
authors.identifier: http://orcid.org/0000-0002-4839-8279
authors.initials: AL
authors.lastname: Silva
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000072000:NF-KappaB Inhibitor alpha / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D019311:Staurosporine / Q000494:pharmacology; D000072637:Thyroid Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014162:Transfection; D020830:rac1 GTP-Binding Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: C530104:CCND1 protein, human; D016328:NF-kappa B; C107953:RAC1 protein, human; D019938:Cyclin D1; D000072000:NF-KappaB Inhibitor alpha; D020830:rac1 GTP-Binding Protein; D019311:Staurosporine