title: TRAIL up-regulation must be accompanied by a reciprocal PKCε down-regulation during differentiation of colonic epithelial cell: implications for colorectal cancer cell differentiation.
abstract: 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.
authors.affiliation: Department of Human Anatomy, Pharmacology & Forensic Medicine, University of Parma, Parma, Italy.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Gobbi
authors.forename: Daniela
authors.initials: D
authors.lastname: Di Marcantonio
authors.forename: Cristina
authors.initials: C
authors.lastname: Micheloni
authors.forename: Cecilia
authors.initials: C
authors.lastname: Carubbi
authors.forename: Daniela
authors.initials: D
authors.lastname: Galli
authors.forename: Mauro
authors.initials: M
authors.lastname: Vaccarezza
authors.forename: Giovanna
authors.initials: G
authors.lastname: Bucci
authors.forename: Marco
authors.initials: M
authors.lastname: Vitale
authors.forename: Prisco
authors.initials: P
authors.lastname: Mirandola
mesh_terms: D017209:Apoptosis; D002087:Butyrates / Q000494:pharmacology; D002454:Cell Differentiation; D003106:Colon / Q000166:cytology*; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D020397:Goblet Cells / Q000166:cytology / Q000502:physiology; D019073:HT29 Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*
chemical_list: D002087:Butyrates; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D051744:Protein Kinase C-epsilon