TRAIL up-regulation must be accompanied by a reciprocal PKCε down-regulationduring differentiation of colonic epithelial cell: implications for colorectalcancer 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 PKCε and TRAIL are involved in the
differentiation of other cell types like hematopoietic stem cells. Although the
role of PKCε and TRAIL in the gastrointestinal system is unclear, it has been
observed that PKCε 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 PKCε and TRAIL in human colon
mucosa: CECs at the bottom of the colonic crypts show high levels of PKCε, being
negative for TRAIL expression. On the contrary, luminal CECs are positive for
TRAIL, while negative for PKCε. Indeed, TRAIL- and butyrate-induced
differentiation of the human colorectal cancer cell line HT29 requires the
decrease of PKCε 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 PKCε must be reciprocally regulated to ensure physiological CEC
differentiation starting from the stem cell pool, and that the down-regulation of
PKCε is however critical for the differentiation and apoptosis of cancer cells.