RESUMO
Nm23-H1 is a metastasis suppressor gene whose overexpression is associated with both reduced cell motility in various cancers and increased metastatic potential in neuroblastomas, osteosarcomas, and hematological malignances. We previously reported that Nm23-H1 exerts tumor suppressor action in prostate cancer cells and that h-Prune, which is overexpressed in various tumor types, binds Nm23-H1. Moreover, blockage of the Nm23-H1/h-Prune interaction with a competitive permeable peptide (CPP) attenuates migration of breast and neuroblastoma cells. This series of events suggests that the Nm23-H1/h-Prune protein complex regulates cancer progression and that its specific impairment could be a new therapeutic strategy in oncology. We found that CPP leads to inhibition of the AKT/mTORv and NF-kBv signaling pathways and also activates apoptosis. To obtain a proof-of-concept of our hypothesis, we used a xenograft model of prostate cancer to evaluate whether impairment of this complex using CPP results in an anti-tumoral effect. Using a mouse orthotopic model with bioluminescent imaging, we show evidences that CPP reduces prostate cancer metastases formation. In conclusion, CPP being able to impair formation of the h-Prune/Nm23-H1 complex holds promise for the treatment of prostate cancer.
Assuntos
Proteínas de Transporte/metabolismo , Peptídeos Penetradores de Células/uso terapêutico , Nucleosídeo NM23 Difosfato Quinases/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Adenoviridae/genética , Animais , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Peptídeos Penetradores de Células/farmacologia , Humanos , Masculino , Camundongos , Camundongos Nus , Nucleosídeo NM23 Difosfato Quinases/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
H-Prune hydrolyzes short-chain polyphosphates (PPase activity) together with an hitherto cAMP-phosphodiesterase (PDE), the latest influencing different human cancers by its overexpression. H-Prune promotes cell migration in cooperation with glycogen synthase kinase-3 (Gsk-3ß). Gsk-3ß is a negative regulator of canonical WNT/ß-catenin signaling. Here, we investigate the role of Gsk-3ß/h-Prune complex in the regulation of WNT/ß-catenin signaling, demonstrating the h-Prune capability to activate WNT signaling also in a paracrine manner, through Wnt3a secretion. In vivo study demonstrates that h-Prune silencing inhibits lung metastasis formation, increasing mouse survival. We assessed h-Prune levels in peripheral blood of lung cancer patients using ELISA assay, showing that h-Prune is an early diagnostic marker for lung cancer. Our study dissects out the mechanism of action of h-Prune in tumorigenic cells and also sheds light on the identification of a new therapeutic target in non-small-cell lung cancer.