Impact of Akt1 polymorphism on DNA damage, Btg2 expression, and risk of colorectal cancer development

Akt1 inactivation and risk of colorectal cancer

Abstract

Background. Akt, also called protein kinase B, is a serine-threonine kinase that functions as a mediator of PI3K-Akt-mTOR signaling pathway and plays an important role in an array of cellular processes. Many single nucleotide polymorphisms (SNP) in Akt gene have been observed to be associated with various types of cancers. In the current research the association of a functional SNP rs1130233 in Akt, depicting G to A transition, was studied with Akt activation, DNA damage, an early response B-cell translocation gene 2 (Btg2) expression and risk of colorectal cancer (CRC) development.

Patients and methods. A total 197 normal individuals and 200 CRC patients were genotyped for SNP rs1130233. Akt expression, activation and Btg2 expression were determined in GG, AG and AA genotype carriers. DNA damage was determined through comet assay.

Results. The heterozygous AG genotype (55.67%) was more prevalent in the local population compared to homozygous wild type GG (37.78%) and homozygous mutant AA genotypes (6.55). Moreover, AG and AA alleles were observed to be significant contributors (P=0.01, OR=1.80, CI=1.18 to 2.74, and P=0.001, OR=5.00, CI=1.90 to 13.18, respectively) in increasing the risk of CRC.  The immunoblot analysis revealed that G to A transition decreased the expression and activation of Akt. Moreover, AG and AA genotypes of Akt1 rs1130233 showed a significant increase in DNA damage and Btg2 expression.

Conclusion. The data concludes that G to A substitution is a risk factor for CRC development involving a decrease in Akt expression and activation and increase in DNA damage.