AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis.
The inhibition of apoptosis is a critical event in the development of colorectal malignancies, although the mechanism(s) remain incompletely understood. The anti-apoptotic proto-oncogene, AKT, has been implicated in the molecular pathogenesis of a variety of human malignancies; however, no data exist on the role of AKT in colon carcinogenesis. We therefore evaluated the presence of AKT in human and experimental colon neoplasms by immunohistochemistry. Normal colonic mucosa and hyperplastic polyps exhibited no significant AKT expression, in marked contrast to the dramatic AKT immunoreactivity seen in colorectal cancers (57% positive) and in both human colorectal cancer cell lines examined. Importantly, AKT was also detected in 57% of the adenomas examined, implicating overexpression of this proto-oncogene as an early event during colon carcinogenesis. Moreover, in the rodent-carcinogen model, azoxymethane (AOM)-treatment induced AKT expression in premalignant rat colonocytes. Tumors that evolve via different genetic pathways displayed a lower incidence of AKT overexpression. Indeed, only 22% of mismatch repair defective tumors and 42% of AOM-induced rodent tumors upregulated AKT. Staining with an antibody specific for AKT 2 duplicated findings with the AKT 1&2 antibody, suggesting that AKT 2 was the predominant isoform involved in colon carcinogenesis. Furthermore, utilizing an antibody that specifically recognizes the serine-473 phosphorylated form of AKT, we observed that activated AKT was detectable in the neoplastic but not normal epithelium. In summary, our immunohistochemical analysis indicates AKT overexpression occurs frequently during human colon carcinogenesis, but is less common in colon cancers with microsatellite instability. The early inhibition of apoptosis during sporadic colon carcinogenesis may be related, at least partly, to the overexpression of AKT.
Roy
Hemant K
HK
Department of Internal Medicine, University of Nebraska Medical Center/Eppley Cancer Institute, 982000 Nebraska Medical Center, Omaha, NE 68198-2000, USA. hroy@unmc.edu
Olusola
Bola F
BF
Clemens
Dahn L
DL
Karolski
William J
WJ
Ratashak
Anne
A
Lynch
Henry T
HT
Smyrk
Thomas C
TC
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D003110:Colonic Neoplasms / Q000276:immunology / Q000378:metabolism*; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D017346:Protein Serine-Threonine Kinases; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000276:immunology / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D013997:Time Factors; D014407:Tumor Cells, Cultured
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; C494918:AKT1 protein, human; C494921:AKT2 protein, human; C494920:Akt1 protein, rat; C494923:Akt2 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt