Emerging role of the β-catenin-PPARγ axis in the pathogenesis of colorectal cancer

Figure 4 Molecular interactions between Wnt/β-catenin and PPARγ signaling in colorectal cancer cells. The Wnt/β-catenin and PPARγ signal transduction pathways likely act in a coordinated manner to ensure epithelial cells a balance between growth and differentiation. In this condition, β-catenin is targeted by PPARγ for phosphorylation and subsequent degradation. In CRC, the Wnt pathway is generally overactive and β-catenin is stabilized and translocates to the nucleus to activate Wnt target genes. In a “Wnt on” state, PPARγ protein is generally elevated likely due to high β-catenin levels. The selective inhibition of PPARγ target genes expression may be ascribed to different mechanisms: interaction of β-catenin with PPARγ-associated transcriptional complexes recruited on the DNA that results in transcription inhibition or in squelching of critical PPARγ coactivators through the alternative binding with β-catenin. Our data and those already published suggest a hypothetical model whereby a ligand-bound PPARγ suppresses Wnt/β-catenin signaling in a cancer-cell context dependent manner by: (1) activating transcription of its own target genes; (2) facilitating the GSK3β-dependent degradation of β-catenin; and (3) competing in the nucleus with transcription factors such as LEF/TCFs in blocking prosurvival β-catenin target genes also in cells harboring a mutated APC.