Protein kinase C isoforms in the chemopreventive effects of a novel vitamin D3 analogue in rat colonic tumorigenesis.
OBJECTIVE
We recently showed that dietary supplementation with an analogue of 1alpha,25-dihydroxy-vitamin D3, 1alpha,25-dihydroxy-16-ene-23-yne-26,27 F6-vitamin D3 (RO24-5531), reduced the incidence of colonic tumors in rats treated with azoxymethane (AOM). The aim of this study was to determine whether alterations in specific isoforms of protein kinase C (PKC) are involved in this phenomenon.


METHODS
Protein abundance and subcellular distribution of several PKC isoforms were examined and compared in AOM-induced tumors of rats fed control and RO24-5531-supplemented diets.


RESULTS
In both AOM-induced colonic adenomas and carcinomas, a significant down-regulation of PKC-alpha, -delta, and -zeta and an up-regulation of PKC-beta11 were found compared with control colonocytes. Dietary RO24-5531 preserved the expression of PKC-zeta and increased the abundance of PKC-epsilon in carcinogen-induced adenomas.


CONCLUSIONS
Because identical changes in specific isoforms of PKC were found in AOM-induced adenomas and carcinomas, these alterations may be involved in the early stage(s) of colonic malignant transformation. Moreover, the ability of RO24-5531 to block the changes in PKC-zeta induced by AOM, as well as to up-regulate PKC-epsilon, may underlie its ability to prevent adenomas from progressing to carcinomas.
Wali
R K
RK
Department of Medicine, University of Chicago Hospitals and Clinics, Illinois. USA.
Bissonnette
M
M
Khare
S
S
Aquino
B
B
Niedziela
S
S
Sitrin
M
M
Brasitus
T A
TA
D000230:Adenocarcinoma / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D000236:Adenoma / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001397:Azoxymethane; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D018890:Chemoprevention; D003106:Colon / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D015536:Down-Regulation; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D015854:Up-Regulation
D016588:Anticarcinogenic Agents; D007527:Isoenzymes; C086492:Ro 24-5531; D011493:Protein Kinase C; D002117:Calcitriol; D001397:Azoxymethane