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.
Highlights
The AKT kinases (AKT1, AKT2, AKT3) represent the primary downstream end-point of the phosphoinositide 3-kinase (PI3K) pathway, regulating proliferation, survival, metabolism and invasion [1] that are frequently activated in human cancer [2], [3, 4]
We investigated whether mutant AKT1-E17K transforms lung epithelial cells using human normal bronchial epithelial cells immortalized by infection with Adenovirus 12/SV40 hybrid virus (BEAS-2B) [34]
In agreement with the results of AKT activation, the difference in the proliferation rate between BEAS-AKT1-E17K cells and BEAS-2B cells were mock-transduced (BEAS-C) or BEAS-AKT1-WT cells was predominantly observed under conditions of growth factor deprivation. These results indicate that mutant AKT1-E17K, but not wild type AKT1 expressed at similar level, is able to promote anchorage-dependent proliferation of human bronchial epithelial cells, especially under stressful conditions
Summary
The AKT kinases (AKT1, AKT2, AKT3) represent the primary downstream end-point of the phosphoinositide 3-kinase (PI3K) pathway, regulating proliferation, survival, metabolism and invasion [1] that are frequently activated in human cancer [2], [3, 4]. In 2007 an oncogenic somatic mutation in the pleckstrin homology (PH) domain of AKT1 that results in glutamic acid to lysine substitution at residue 17 (E17K) was reported in breast, ovarian and colon cancer [8]. This change increases the binding of AKT1 to PI (4, 5) P2, enhancing plasma membrane recruitment and activation [8, 9]. Endogenous AKT1-E17K mutant detected in lung cancer cells shows enhanced membrane localization [10], which results in the activation of downstream signalling [8, 10]. In lung cancer AKT1 mutations are rare, with overall reported frequency of 0.6–2% [10, 13, 18,19,20,21]
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