TRAIL up-regulation must be accompanied by a reciprocal PKCε down-regulation during differentiation of colonic epithelial cell: Implications for colorectal cancer cell differentiation

PKC isoenzymes play central roles in various cellular signalling pathways, participating in a variety of protein phosphorylation cascades that regulate/modulate cellular structure and gene expression. It has been firmly established that several isoforms of PKC have a role in the regulation of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) activity. Our interest in probing the role of the epsilon isoform of PKC in the colonic cell differentiation stems from the discovery that PKCe and TRAIL are involved in the differentiation of other cell types like hematopoietic stem cells. Although the role of PKCe and TRAIL in the gastrointestinal system is unclear, it has been observed that PKCe has oncogenic activity in colon epithelial cells (CEC), while TRAIL increases the death of intestinal epithelial cells during inflammation. Here we demonstrate a reciprocal expression of PKCe and TRAIL in human colon mucosa: CECs at the bottom of the colonic crypts show high levels of PKCe, being negative for TRAIL expression. On the contrary, luminal CECs are positive for TRAIL, while negative for PKCe. Indeed, TRAIL- and butyrate-induced differentiation of the human colorectal cancer cell line HT29 requires the decrease of PKCe expression, whose absence in turn increases cell sensitivity to TRAIL-induced apoptosis. Moreover, TRAIL preferentially promotes HT29 differentiation into goblet cells. Taken together, this data demonstrate that TRAIL and PKCe must be reciprocally regulated to ensure physiological CEC differentiation starting from the stem cell pool, and that the down-regulation of PKCe is however critical for the differentiation and apoptosis of cancer cells. J. Cell. Physiol. 227: 630638, 2012. (C) 2011 Wiley Periodicals, Inc.