Diverse involvement of isoforms and gene aberrations of Akt in human lung carcinomas

Emerging evidence confirms a central role of Akt in cancer. To evaluate the relative contribution of deregulated Akt and their clinicopathological significance in lung carcinomas, overexpression, activation of Akt and AKT gene increases were investigated. Immunohistochemical staining for 108 cases revealed overexpression of total Akt, Akt1, Akt2 and Akt3 in 61.1, 47.2, 40.7 and 23.1%, respectively, and phosphorylated Akt in 42.6% of cases. Expression of total Akt, Akt2 and Akt3 were frequently observed in small cell carcinoma, but phosphorylated Akt and Akt1 were more frequently observed in squamous cell carcinoma. FISH analysis to evaluate gene increases of AKT 1‐3 revealed amplification of AKT 1 in 4.2% and AKT 1 increase by polysomy of chromosome 14 in 27.3% of cases. For AKT 2, amplification was observed in 3.2% and polysomy of chromosome 19 in 26.3% of cases. AKT 3 increase was observed in 40.0% of cases only by polysomy of chromosome 1. Although “ FISH ‐positive” AKT 1 and AKT 2 gene increases (amplification/high‐level polysomy) were found exclusively in the cases overexpressing total Akt, Akt1 or Akt2, respectively, AKT 3 increase was irrelevant of Akt3 expression. Statistically, expressions of Akt2, p‐Akt and cytoplasmic‐p‐Akt were correlated with lymph node metastasis ( P  = 0.0479, P  = 0.0371 and P  = 0.0310, respectively). Although AKT 1 and AKT 2 gene increase showed positive correlation with, or trend towards a positive correlation with tumor size ( P  = 0.0430, P  = 0.0590, respectively), AKT 3 did not. In conclusion, Akt isoforms are differentially involved in the pathological phenotype of lung carcinoma in a diverse manner. Because abnormality of Akt1/ AKT 1 and Akt2/ AKT 2 correlated with clinicopathological profiles, Akt1/2‐specific targeting may open a novel therapeutic window for the group showing Akt deregulation.