Activation of the Serine/Threonine Protein Kinase AKT During the Progression of Colorectal Neoplasia

BackgroundAKT has been identified as a major regulator of cell proliferation, tumorigenesis, and apoptosis. In this study, we evaluated changes in the activity of AKT during colorectal cancer (CRC) progression.Materials and MethodsWe used stage-oriented human CRC tissue microarrays, including 99 invasive carcinomas, 28 tubular adenomas, and 18 samples of normal colonic mucosa. The tissue array slides were stained with a mouse monoclonal antiphospho-AKT antibody using the avidin-biotin complex method.ResultsActivation of AKT was detected mostly in the invasive carcinomas. Sixty-three percent of carcinomas demonstrated strong to moderate AKT activity. Seven percent of carcinomas were phospho-AKT (P-AKT) negative, and 30% (30 of 99) were p-AKT weakly positive. Conversely, 78% of normal colonic mucosas were p-AKT negative, and only 4 samples stained weakly for p-AKT. Eighty-two percent of adenomas were weakly positive for p-AKT, 1 was p-AKT negative, and none exhibited strong or moderate p-AKT stain. At a significance level of .05, we found that the distribution of p-AKT stain scores for cancer was shifted to the right of adenoma (P < .0001) and normal (P < .0001) and for adenoma was shifted to the right of normal (P < .0001). AKT activation did not correlate with tumor stage (P = .28), lymph node metastasis (P = .45), lymphatic invasion (P = .46), or distant metastasis (P = .34).ConclusionThis study shows increasing activation of AKT during CRC progression. This finding suggests a role of p-AKT in colorectal carcinogenesis and provides a rationale for using p-AKT inhibitor API-2/triciribine, which is currently under clinical investigation for the treatment of CRC.