Although AKT ⁄ protein kinase B is constitutively active in nonsmall cell lung cancer (NSCLC) cells and is an attractive target for enhancing the cytotoxicity of therapeutic agents, the distinct roles of the AKT isoforms in NSCLC are largely unknown. In the present study, we investigated the roles of AKT1 and AKT2 in NSCLC cells using RNAi. The siRNA targeting of AKT1 or AKT2 effectively decreased protein levels of AKT1 and AKT2, respectively, in A549 and H460 cells. Cisplatin treatment of these cells increased apoptotic cell death compared with control. The siRNA-induced knockdown of AKT1 in H460 cells significantly decreased basal MEK⁄ ERK1 ⁄ 2 activity, resulting in nuclear factor-κB activation, whereas knockdown of AKT2 resulted in anti-apoptotic Bcl-2 family protein MCL-1 (MCL-1) cleavage, the collapse of mitochondrial membrane potential, cytochrome c release, and activation of the caspase cascade. Consequently, both siRNA treatments enhanced the chemosensitivity of H460 cells to cisplatin. However, neither AKT1 nor AKT2 siRNA treatment had any effect of p27 expression, and although both treatments tended to induced G₂ ⁄M phase arrest, the effect was not statistically significant. Treatment with AKT1 siRNA markedly decreased colony formation growth and migration, but AKT2 siRNA had no significant effects on these parameters. These data suggest that AKT1 and AKT2 both contribute to cell survival, albeit via different mechanisms, and that the effects on cell growth and migration are predominantly regulated by AKT1. These findings may aid in refining targeted strategies for the inhibition of AKT isoforms towards the sensitization of NSCLC cells to therapeutic agents.

Study Type – Prognosis (case series)
Level of Evidence 4 OBJECTIVE To investigate the rate of pathologically confirmed unfavourable prostate cancers among Korean men who fulfilled the contemporary Epstein criteria for clinically insignificant prostate cancer. PATIENTS AND METHODS This was a retrospective study of 131 Korean men who underwent radical prostatectomy (RP) for clinically insignificant prostate cancer as defined by contemporary Epstein criteria. We assessed the percentage of unfavourable prostate cancer (pathological Gleason sum ≥7 and/or extraprostatic extension [EPE]) among these men and tried to identify useful predictors for such unfavourable tumour profiles using uni‐ and multivariate analyses. RESULTS Among 131 men with clinically insignificant prostate cancer, 40 (30.5%) had pathological Gleason ≥7 tumours after RP. Of these 40 men, four (3.1%) also had EPE on examination of RP specimen. All those who did not have Gleason score upgrading after RP had organ‐confined disease from examination of RP specimen. Overall, 40 (30.5%) of the 131 men who fulfilled the contemporary Epstein criteria for clinically insignificant prostate cancer before RP had pathologically unfavourable disease. Among our patients, no significant preoperative predictor of pathologically unfavourable disease was identified using uni‐ and multivariate analyses. CONCLUSION Our results showed that a significant proportion of contemporary Korean patients who meet all the conditions of the contemporary Epstein criteria for prediction of clinically insignificant prostate cancer might actually harbour prostate cancer with unfavourable pathological features. Such findings should be considered when treatment options are contemplated based upon the Epstein criteria among Asian patients.