AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis

Hemant K. Roy, Bola F. Olusola, Dahn L. Clemens, William J. Karolski, Anne Ratashak, Henry T. Lynch, Thomas C. Smyrk

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)201-205
Number of pages5
JournalCarcinogenesis
Volume23
Issue number1
StatePublished - 2002

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Proto-Oncogenes
Colon
Carcinogenesis
Azoxymethane
Neoplasms
Colonic Neoplasms
Experimental Neoplasms
Antibodies
Colorectal Neoplasms
Rodentia
Apoptosis
Microsatellite Instability
DNA Mismatch Repair
Polyps
Carcinogens
Adenoma
Serine
Protein Isoforms
Mucous Membrane
Epithelium

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

Roy, H. K., Olusola, B. F., Clemens, D. L., Karolski, W. J., Ratashak, A., Lynch, H. T., & Smyrk, T. C. (2002). AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis. Carcinogenesis, 23(1), 201-205.

AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis. / Roy, Hemant K.; Olusola, Bola F.; Clemens, Dahn L.; Karolski, William J.; Ratashak, Anne; Lynch, Henry T.; Smyrk, Thomas C.

In: Carcinogenesis, Vol. 23, No. 1, 2002, p. 201-205.

Research output: Contribution to journalArticle

Roy, HK, Olusola, BF, Clemens, DL, Karolski, WJ, Ratashak, A, Lynch, HT & Smyrk, TC 2002, 'AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis', Carcinogenesis, vol. 23, no. 1, pp. 201-205.
Roy HK, Olusola BF, Clemens DL, Karolski WJ, Ratashak A, Lynch HT et al. AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis. Carcinogenesis. 2002;23(1):201-205.
Roy, Hemant K. ; Olusola, Bola F. ; Clemens, Dahn L. ; Karolski, William J. ; Ratashak, Anne ; Lynch, Henry T. ; Smyrk, Thomas C. / AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis. In: Carcinogenesis. 2002 ; Vol. 23, No. 1. pp. 201-205.
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