Anti-proliferative activity of protein kinase C in apical compartments of human colonic crypts: Evidence for a less activated protein kinase C in small adenomas

Abstract

The protein‐kinase‐C (PKC) family of iso‐enzymes regulates mitogenic signal transduction in colorectal‐cell lines. Its function in human colonic mucosal proliferation is controversial. Our study investigated the role of PKC with regard to proliferation and changes of PKC iso‐enzyme expression in colonic biopsies compared with small adenomas. In short‐term tissue‐culture experiments of colonic mucosal biopsies, we found reduced S‐phase labeling in the 2 apical compartments of longitudinally sectioned crypts when PKC was activated by 200 nM of the phorbol ester TPA (n = 8). Thus, PKC inhibited growth of differentiated colonocytes which may influence cell homeostasis in colonic crypts. Furthermore, we have determined the expression of PKCα, ‐β1, ‐β2, ‐δ and ‐ϵ in colonic adenomas smaller than 1 cm in diameter of 18 patients and found a significant increase of PKCα in the cytosolic fraction and decreased membrane levels of PKCβ2 in adenomas compared to normal, neighboring mucosa while protein levels of PKCβ1, ‐δ and ‐ϵ were not altered. Moreover PKCδ but not PKCα mRNA expression was significantly lowered in adenoma tissue in 7 patients, as determined by ribonuclease‐protection analysis. Changes in the regulation patterns of PKC isoforms suggest a decreased activation state of PKC even in small adenomas. This is compatible with an anti‐proliferative function of PKC serving to protect mucosa from expanding mutated cells. Int. J. Cancer 80:47–53, 1999. © 1999 Wiley‐Liss, Inc.

Butyrate-induced alterations of phosphoinositide metabolism, protein kinase C activity and reduced CD44 variant expression in HT-29 colon cancer cells

“…Activation of PKC was reported to induce differentiation in various cell types (41,42). Overexpression of PKCßII in colonic epithelium seems to results in hyperproliferation and an increased susceptibility to carcinogenesis with an early increase in carcinogenesis, whereas PKC was downregulated in colonic tumors (43,44).…”

The Role of Protein Kinase C Isoforms in Modulating Injury and Repair of the Intestinal Barrier

“…PKC isoforms in the gastrointestinal tract are involved in several vital intracellular pathways, including cell proliferation/cytostasis (Batlle et al, 1998;Verstovsek et al, 1998;Assert et al, 1999;Umar et al, 2000), cell differentiation (Abraham et al, 1998;Verstovsek et al, 1998;Frey et al, 2001), apoptosis (Chang and Tepperman, 2001;Frey et al, 2001), cell adhesion (Batlle et al, 1998;Hollande et al, 2003), membrane remodeling (Song et al, 1999(Song et al, , 2002, epithelial migration (Andre et al, 1999), transepithelial permeability (Marano et al, 2001), ion secretion (Van den Berghe et al, 1992;Yoo et al, 2001), receptor and brush border enzyme expression (Murray et al, 2002), cytoskeletal modulation (Fasano et al, 1995;Banan et al, 2002aBanan et al, ,c,d, 2003aBanan et al, ,b, 2004a, tight junction modification , and epithelial responses to inflammatory Tepperman, 2001, 2003), cytotoxic Chang and Tepperman, 2001), and carcinogenic (Pongracz et al, 1995;Murray et al, 1999Murray et al, , 2002Perletti et al, 1999;Mullin et al, 2000) mediators. These multiple roles suggest that this group of enzymes is involved in the regulation of the health and damage of epithelial cells and the intestinal barrier.…”

“…Studies show that increases in the total amount of PKC enzyme is associated with the cessation of cell proliferation and increasing cell maturation (Assert et al, 1999). Several investigators noted that there is a trend toward an increase in PKC-␣ as epithelial cells move from the mitotic phase in the crypt to the differentiating phase in the villous (Verstovsek et al, 1998).…”

Targeting Protein Kinase C: New Therapeutic Opportunities Against High-Grade Malignant Gliomas?

“…For instance, PKCα activity levels seem to be increased in breast cancers [39] and malignant gliomas [40], but underexpressed in colon cancers [41], suggesting that this PKC isoform acts as an oncogene in the former, and as an anti-oncogene in the latter cases. However, PKCα overexpression in cultured MCF-10A nonmetastatic human breast cancer cells led to suppression of proliferation, while at the same time endowing the cells with properties consistent with a metastatic phenotype [42].…”