GSK-3β-mediated fatty acid synthesis enhances epithelial to mesenchymal transition of TLR4-activated colorectal cancer cells through regulation of TAp63

Abstract

Glycogen synthase kinase-3 beta (GSK-3 beta) in cancer cells is a critical regulatory component of both cellular metabolism and epithelial-mesenchymal transition (EMT) processes via regulation of the beta-catenin/E-cadherin and phosphoinositide 3-kinase (PI3K)/AKT signaling pathway. Lipogenesis of cancer cells also plays a critical role in survival and metastasis. We investigated the role of GSK-3 beta-mediated intracellular fatty acid synthesis to control EMT in TLR4-activated colorectal cancer cells and the underlying regulatory mechanism. Engagement of TLR4 with lipopolysaccharide (LPS) in colon cancer cells promoted the induction of phosphorylated GSK-3 beta and related lipogenic enzymes as well as the expression of CD74, CD44 and macrophage inhibitory factor (MIF), but decreased expression of transcriptionally active p63 (TAp63). In addition, targeted inhibition of GSK-3 beta using SB216763 was accompanied by decreased intracellular fatty acid synthesis and blockage of CD74 and CD44 expression, whereas it reversed the level of TAp63. Although TAp63 overexpression had no effect on the expression of CD74 and CD44 in LPS-treated colon cancer cells, GSK-3 beta-dependent fatty acid synthesis and invasive activity were significantly suppressed. Notably, inhibition of CD44 or CD74 by siRNA not only attenuated de novo lipogenesis and migratory activity but also restored the expression of TAp63 in LPS-activated colon cancer cells. These results suggest that TAp63-mediated GSK-3 beta activation induced by TLR4 stimulation triggers migration and invasion of colon cancer cells through the regulation of lipid synthesis and GSK-3 beta-mediated CD74/CD44 expression could be a target to control fatty acid-related EMT process through the modulation of TAp63 expression.