Sodium butyrate-induced differentiation of human LIM2537 colon cancer cells decreases GSK-3beta activity and increases levels of both membrane-bound and Apc/axin/GSK-3beta complex-associated pools of beta-catenin.
Analysis of the glycogen synthase kinase-3beta (GSK-33) 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-3beta activity in the treated cells (P < 0.028, n = 3). Decreases in GSK-3beta activity were paralleled by stabilization of cytoplasmic beta-catenin, a hallmark of Wnt signaling. However, in contrast to Wnt signaling, expression of the beta-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 beta-catenin was increased in the sodium butyrate-treated cells. This suggests that, in the context of cellular differentiation, increases in beta-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 beta-catenin available for cell adhesion.
Vincan
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Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, East Melbourne, Victoria, Australia. e.vincan@pmci.unimelb.edu.au
Leet
C S
CS
Reyes
N I
NI
Dilley
R J
RJ
Thomas
R J
RJ
Phillips
W A
WA
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D060466:Axin Protein; D015820:Cadherins / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002448:Cell Adhesion; D002454:Cell Differentiation; D002462:Cell Membrane / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000188:drug therapy*; D019938:Cyclin D1 / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000096:biosynthesis*; D019084:Fluorescent Antibody Technique, Indirect; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D011233:Precipitin Tests; D011485:Protein Binding; D011486:Protein C / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012097:Repressor Proteins; D015398:Signal Transduction; D012978:Sodium Oxybate / Q000494:pharmacology*; D013997:Time Factors; D015534:Trans-Activators; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D051176:beta Catenin
D060466:Axin Protein; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D015820:Cadherins; D003598:Cytoskeletal Proteins; D011486:Protein C; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; D015534:Trans-Activators; D051176:beta Catenin; D019938:Cyclin D1; D012978:Sodium Oxybate; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D000469:Alkaline Phosphatase