SHORT-CHAIN FATTY ACID-INITIATED CELL-CYCLE ARREST AND APOPTOSIS OF COLONIC EPITHELIAL-CELLS IS LINKED TO MITOCHONDRIAL-FUNCTION

Butyrate, a short-chain fatty acid produced during microbial fermentat ion of fiber, induces growth arrest, differentiation, and apoptosis of colonic epithelial cells in vitro, and our prior work has shown that this induction is tightly linked to mitochondrial activity, Here we de monstrate that 12 h following induction, SW620 human colonic carcinoma cells accumulate simultaneously in G(0)-G(1) and G(2)-M of the cell c ycle. Four h later, during this C-0-G(1) to G(2)-M arrest, cells begin to undergo apoptosis, Using a series of unrelated agents that modulat e mitochondrial functions, we demonstrate that mitochondrial electron transport and membrane potential are critical in initiation of this bu tyrate-mediated growth arrest and apoptosis. Colonic tumorigenesis is characterized by abnormalities in proliferation, apoptosis, and mitoch ondrial activities. Thus, butyrate may reduce risk for colon cancer by inducing a pathway that enhances mitochondrial function, ultimately r esulting in initiation of growth arrest and apoptosis of colonic epith elial cells.