Activation of the serine/threonine protein kinase AKT during the progression of colorectal neoplasia.
BACKGROUND
AKT 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.


METHODS
We 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.


RESULTS
Activation 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).


CONCLUSIONS
This 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.
Saglam
Ozlen
O
Anatomic Pathology, Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL 33612-9497, USA.
Garrett
Christopher R
CR
Boulware
David
D
Sayegh
Zena
Z
Shibata
David
D
Malafa
Mokenge
M
Yeatman
Timothy
T
Cheng
Jin Q
JQ
Sebti
Said
S
Coppola
Domenico
D
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000236:Adenoma / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis*; D046888:Tissue Array Analysis; D015854:Up-Regulation
D051057:Proto-Oncogene Proteins c-akt