Suppression of polyamine catabolism by activated Ki‐ras in human colon cancer cells

Publisher Website
Google Scholar
Abstract
An activated Ki-ras was expressed in the human colon adenocarcinoma cell line Caco-2 to study the effects of Ki-ras oncogene on polyamine metabolism during gastrointestinal tumorigenesis. Multiple clones selected for expression of the mutant Ki-ras transgene displayed a suppression of transcription of a key catabolic enzyme in polyamine catabolism spermidine/spermine N1-acetyltransferase (SSAT). Gene expression analysis, with cDNA microarrays, showed that Ki-ras transfected clones had decreased levels of expression, compared to mock transfected cells, of peroxisome proliferator-activated receptor gamma (PPARγ), a member of the nuclear hormone receptor family and an important regulator of cell proliferation and differentiation. The activated Ki-ras suppressed SSAT expression by a mechanism involving the PPARγ response element (PPRE) located at +48 bp relative to the transcription start site of the SSAT gene. Transient expression of the PPARγ protein in Ki-ras expressing Caco-2 clones, or treatment with the PPARγ ligand ciglitazone, led to an increase in the SSAT promoter activity. A MEK1/2 inhibitor PD98059 induced transcription of both PPARγ and SSAT genes in the activated Ki-ras clones, suggesting that the mitogen-activated protein kinases (MAPKs) were involved in the regulation of SSAT expression by PPARγ. We concluded that mutated Ki-ras suppressed SSAT via a transcriptional mechanism involving the PPARγ signaling pathway.