Mutant AKT1-E17K is oncogenic in lung epithelial cells
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Carmela De Marco1,2, Donatella Malanga1,2, Nicola Rinaldo2, Fernanda De Vita2, Marianna Scrima2, Sara Lovisa3, Linda Fabris3, Maria Vincenza Carriero4, Renato Franco4, Antonia Rizzuto5, Gustavo Baldassarre3, Giuseppe Viglietto1,2
1Department of Experimental and Clinical Medicine, University “Magna Graecia”, Catanzaro, Italy
2BIOGEM-Institute of Genetic Research, Ariano Irpino (AV), Italy
3Experimental Oncology 2, Centro di Riferimento Oncologico, Aviano (PN), Italy
4Experimental Oncology, IRCCS Fondazione Pascale, Napoli, Italy
5Department of Medical and Surgical Sciences, University “Magna Graecia” Medical School, Catanzaro, Italy
Giuseppe Viglietto, e-mail: firstname.lastname@example.org
Keywords: lung cancer, AKT1-E17K, human lung epithelial cells, p27
Received: April 03, 2015 Accepted: May 13, 2015 Published: May 25, 2015
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.
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