RESUMO
NF-κB is a transcription factor involved in the regulation of multiple physiological and pathological cellular processes, including inflammation, cell survival, proliferation, and cancer cell metastasis. NF-κB is frequently hyperactivated in several cancers, including triple-negative breast cancer. Here we show that NF-κB activation in breast cancer cells depends on the presence of the CHORDC1 gene product Morgana, a previously unknown component of the IKK complex and essential for IκBα substrate recognition. Morgana silencing blocks metastasis formation in breast cancer mouse models and this phenotype is reverted by IκBα downregulation. High Morgana expression levels in cancer cells decrease recruitment of natural killer cells in the first phases of tumor growth and induce the expression of cytokines able to attract neutrophils in the primary tumor, as well as in the pre-metastatic lungs, fueling cancer metastasis. In accordance, high Morgana levels positively correlate with NF-κB target gene expression and poor prognosis in human patients.
Assuntos
Neoplasias da Mama/metabolismo , Proteínas de Transporte/metabolismo , Quinase I-kappa B/metabolismo , NF-kappa B/metabolismo , Animais , Apoptose , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/fisiopatologia , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Quinase I-kappa B/genética , Camundongos , Camundongos Endogâmicos BALB C , Chaperonas Moleculares , NF-kappa B/genética , Metástase Neoplásica , Proteínas de Ligação a Fosfato , Transdução de SinaisRESUMO
Morgana is a chaperone protein able to bind to ROCK I and II and to inhibit their kinase activity. Rho kinases are multifunctional proteins involved in different cellular processes, including cytoskeleton organization, centrosome duplication, cell survival and proliferation. In human cancer samples Morgana appears to be either downregulated or overexpressed, and experimental evidence indicate that Morgana behaves both as an oncosuppressor and as a proto-oncogene. Our most recent findings demonstrated that if on the one hand low Morgana expression levels, by inducing ROCK II hyperactivation, cause centrosome overduplication and genomic instability, on the other hand, Morgana overexpression induces tumor cell survival and chemoresistance through the ROCK I-PTEN-AKT axis. Therefore, Morgana belongs to a new class of proteins, displaying both oncogenic and oncosuppressor features, depending on the specific cellular context.
