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Butyrate-induced apoptosis and cell cycle arrest in bovine kidney epithelial cells: Involvement of caspase and proteasome pathways¹

Growth Biology Laboratory, Animal and Natural Resources Institute, ARS, USDA, Beltsville, MD 20705

² Correspondence: 10300 Baltimore Ave., Building 200, Room 209, BARC East (phone: 301-504-7216; fax: 301-504-8623; e-mail: cli{at}anri.barc.usda.gov).

Beyond their nutritional effect, short-chain fatty acids, especially butyrate, modulate cell differentiation, proliferation, motility, and in particular, they induce cell cycle arrest and apoptosis. A bovine kidney epithelial cell line (Madin-Darby bovine kidney; MDBK) was used to investigate the cell cycle regulatory and apoptotic effects of butyrate. Butyrate not only induced apoptosis but also induced cell cycle arrest at the G1/S boundary and M/G2 in MDBK cells (P < 0.01). The cell responses were concentration-dependent (r² = 0.9482, P <0.001). In examining possible mechanisms for the apoptosis and cell cycle arrest induced by butyrate, the results showed that butyrate treatment activates caspase-3 activities and induces accumulation of acetylated histone. At least two proteins, cdc6 and cdk1, become targeted for destruction on butyrate treatment. These two proteins are downregulated (P < 0.01 and P < 0.05, respectively) by proteolytic pathways. Moreover, the proteasome inhibitor MG-132 (carbobenzoxy-L-leucyl-L-leucyl-L-leucinal) reverses the cell cycle arrest induced by butyrate, indicating a multiprotein crosstalk wherein the ubiquitination/ proteasome pathway interacted with the caspase-signaling pathway. Because the proteasome inhibitor MG-132 blocked activation of caspase-3, these results functionally locate the proteasome pathway upstream of the caspase pathway. All these results indicate that butyrate functions as both a nutrient and signaling molecule regulating cell growth and proliferation.

Key Words: Apoptosis • Bovine Kidney Epithelial Cell • Butyrate • Caspase-3 • Cell Cycle • Proteasome

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