ACTIVATION OF PPAR-GAMMA LEADS TO INHIBITION OF ANCHORAGE-INDEPENDENTGROWTH OF HUMAN COLORECTAL-CANCER CELLS

Background & Aims: Peroxisomal proliferator-activated receptor gamma ( PPAR gamma) is a nuclear hormone receptor that provides a direct link between fatty acid metabolism and control of gene transcription. The o bjective of this study was to determine the biological effect(s) of PP AR gamma activation in colorectal carcinoma cells. Methods: PPAR gamma expression and activity were measured in 4 human colon cancer cell li nes using reverse-transcription polymerase chain reaction, immunopreci pitation and immunoblotting, and transient reporter gene assays. The e ffects of activated PPAR gamma in these cell lines were assessed in ce llular proliferation and anchorage-independent growth assays. Flow cyt ometry was used to determine the effects of PPAR gamma activation on p rogression through the cell cycle. Results: PPAR gamma was expressed i n ail 4 colon cancer cell lines examined and was transcriptionally fun ctional in 3 of the 4. Treatment of these cells with a selective PPAR gamma activator (BRL 49653) resulted in inhibition of anchorage-indepe ndent growth. The degree of growth inhibition correlated with the leve l of functional PPAR gamma present. Finally, activation of PPAR gamma resulted in G(1) cell cycle arrest. Conclusions: Activation of the PPA R gamma pathway in colon cancer cells has potent antiproliferative eff ects, suggesting that this nuclear hormone receptor may provide a nove l target for prevention and treatment of colorectal cancer in humans.