3,3 '-diindolylmethane downregulates cyclin D1 through triggering endoplasmic reticulum stress in colorectal cancer cells

Abstract

As a major in vivo condensation product of indole-3-carbinol, which is mostly present in cruciferous vegetables, 3,3'-diindolylmethane (DIM) has been previously reported with anti-proliferative action in different types of cancer by our group and others. To further elucidate these underlying mechanisms, we examined the effect of DIM on cyclin D1, which was aberrantly overexpressed in various cancer cells and tumors. Herein, we found that DIM downregulated cyclin D1 expression in colorectal cancer cells (CRC), which was independent of PPAR gamma expression and protease activity. Furthermore, DIM did not affect cyclin Dl mRNA expression, suggesting DIM modulated cyclin Dl expression at the translational level. Subsequently, blocking eIF2 alpha phosphorylation resulted from endoplasmic reticulum (ER) stress restored cyclin Dl in the presence of DIM. Thus, the present study demonstrates that DIM downregulates cyclin D1 through triggering ER stress in human colorectal cancer cells.