Glucose and cAMP regulation of Wnt/beta-catenin signaling pathway

Abstract

The canonical Wnt/β-catenin signaling pathway is recently identified to regulate cellular metabolism processes and act as a “glucose sensor” in certain cell lines. Results of our laboratory have shown that glucose can increase cAMP levels to regulate the levels of β-catenin protein in INS-1E β-cells. Activation of the canonical Wnt signaling pathway can decrease the rate of β-catenin targeting for ubiquitin-mediated degradation, so the hallmark of the signaling pathway activation is the accumulation of β-catenin protein levels in the cells. Cytoplamic β-catenin proteins can translocate into the nucleus, and binds with LEF/TCF transcription factor to induce Wnt-target gene expression. Dysregulation of Wnt/β-catenin signaling pathway is related to the development of type 2 diabetes mellitus and cancer. Thus, it is important to study the regulation of this pathway in different cell lines. This study investigated the effect of glucose and cAMP on β-catenin protein levels in different cell lines. We demonstrated that glucose did not acutely regulate β-catenin protein levels in GLUTag cells, αTC1-9 cells and three cancer cell lines. However, glucose could have a long-term effect on active and total β-catenin levels in GLUTag cells. We found that forskolin-induced cAMP/PKA signaling pathway could enhance phosphorylation of β-catenin at Serine 552 and Serine 675 in GLUTag cells and three cancer cell lines. Our findings indicated that cAMP signaling pathway can regulate phosphorylated β-catenin levels in different cancer cell lines and the findings have potentially very important implications for the inhibition of Wnt/β-catenin signaling pathway in cancer cell lines.