Sodium Butyrate-Induced Differentiation of Human LIM2537 Colon Cancer Cells Decreases GSK-3β Activity and Increases Levels of Both Membrane-Bound and APC/Axin/GSK-3β Complex-Associated Pools of β-Catenin

Analysis of the glycogen synthase kinase-3β (GSK-3β) activity in several colon cancer cell lines suggested a correlation between comparatively low enzyme activity and moderate to high differentiation status. Treatment of LIM2537 cells, a poorly differentiated colon cancer cell line, with the potent differentiating agent sodium butyrate resulted in 34% reduction in GSK-3β activity in the treated cells (P < 0.028, n = 3). Decreases in GSK-3β activity were paralleled by stabilization of cytoplasmic β-catenin, a hallmark of Wnt signaling. However, in contrast to Wnt signaling, expression of the β-catenin/TCF target genes c-myc and cyclin D1 did not appear to be increased in the sodium butyrate-treated cells. Interestingly, expression of membrane-bound β-catenin was increased in the sodium butyrate-treated cells. This suggests that, in the context of cellular differentiation, increases in β-catenin expression may be sequestered at the cell membrane and suggests that a possible role of sodium butyrate in promoting differentiation may be via increasing the levels of β-catenin available for cell adhesion.