Mutant AKT1-E17K is oncogenic in lung epithelial cells

// Carmela De Marco 1, 2 , Donatella Malanga 1, 2 , Nicola Rinaldo 2 , Fernanda De Vita 2 , Marianna Scrima 2 , Sara Lovisa 3 , Linda Fabris 3 , Maria Vincenza Carriero 4 , Renato Franco 4 , Antonia Rizzuto 5 , Gustavo Baldassarre 3 , Giuseppe Viglietto 1, 2 1 Department of Experimental and Clinical Medicine, University “Magna Graecia”, Catanzaro, Italy 2 BIOGEM-Institute of Genetic Research, Ariano Irpino (AV), Italy 3 Experimental Oncology 2, Centro di Riferimento Oncologico, Aviano (PN), Italy 4 Experimental Oncology, IRCCS Fondazione Pascale, Napoli, Italy 5 Department of Medical and Surgical Sciences, University “Magna Graecia” Medical School, Catanzaro, Italy Correspondence to: Giuseppe Viglietto, e-mail: viglietto@unicz.it Keywords: lung cancer, AKT1-E17K, human lung epithelial cells, p27 Received: April 03, 2015 Accepted: May 13, 2015 Published: May 25, 2015 ABSTRACT The hotspot E17K mutation in the pleckstrin homology domain of AKT1 occurs in approximately 0.6–2% of human lung cancers. In this manuscript, we sought to determine whether this AKT1 variant is a bona-fide activating mutation and plays a role in the development of lung cancer. Here we report that in immortalized human bronchial epithelial cells (BEAS-2B cells) mutant AKT1-E17K promotes anchorage-dependent and -independent proliferation, increases the ability to migrate, invade as well as to survive and duplicate in stressful conditions, leading to the emergency of cells endowed with the capability to form aggressive tumours at high efficiency. We provide also evidence that the molecular mechanism whereby AKT1-E17K is oncogenic in lung epithelial cells involves phosphorylation and consequent cytoplasmic delocalization of the cyclin-dependent kinase (cdk) inhibitor p27. In agreement with these results, cytoplasmic p27 is preferentially observed in primary NSCLCs with activated AKT and predicts poor survival.