ATF3 Mediates Anti-Cancer Activity of Trans-10, cis-12-Conjugated Linoleic Acid in Human Colon Cancer Cells

ABSTRACT

Conjugated linoleic acids (CLA) are a family of isomers of linoleic acid. CLA increases growth arrest and apoptosis of human colorectal cancer cells through an isomer-specific manner. ATF3 belongs to the ATF/CREB family of transcription factors and is associated with apoptosis in colorectal cancer. The present study was performed to investigate the molecular mechanism by which t10, c12-CLA stimulates ATF3 expression and apoptosis in human colorectal cancer cells. t10, c12-CLA increased an apoptosis in human colorectal cancer cells in dose dependent manner. t10, c12-CLA induced ATF3 mRNA and luciferase activity of ATF3 promoter in a dose-dependent manner. The responsible region for ATF3 transcriptional activation by t10, c12-CLA is located between -147 and -1850 of ATF3 promoter. mRNA stability of ATF3 was not affected by t10, c12-CLA treatment. t10, c12-CLA increases GSK3beta expression and suppresses IGF-1-stimulated phosphorylation of Akt. The knockdown of ATF3 suppressed expression of GSK3beta and NAG-1 and PARP cleavage. The results suggest that t10, c12-CLA induces apoptosis through ATF3-mediated pathway in human colorectal cancer cells.