Chemopreventive N-(4-hydroxyphenyl)retinamide (fenretinide) targets deregulated NF-{kappa}B and Mat1A genes in the early stages of rat liver carcinogenesis.
Cell-cycle deregulation is an early event of hepatocarcinogenesis. We evaluated the role of changes in activity of nuclear factor kappaB (NF-kappaB) and some related pathways in this alteration, and the interference of N-(4-hydroxyphenyl)retinamide (HPR), a retinoid chemopreventive for various cancer types, with these molecular mechanisms and the evolution of preneoplastic liver to cancer. Male F344 rats, initiated according to the 'resistant hepatocyte' model of liver carcinogenesis, received weekly 840 nmol of liposomal HPR (SL-HPR)/100 g body wt or empty liposomes, between 5 and 25 weeks after initiation. Inhibition of DNA synthesis and induction of apoptosis occurred in pre-cancerous lesions, 7-147 days after starting SL-HPR, and a decrease in carcinoma incidence and multiplicity was observed 25 weeks after arresting treatment. An increase in NF-kappaB expression and binding activity, and under-expression of the inhibitor kappaB-alpha (IkappaB-alpha) were found in preneoplastic liver and neoplastic nodules, 5 and 25 weeks after initiation, respectively. These lesions also showed low expression of Mat1A and low activity of methionine adenosyltransferase I/III, whose reaction product, S-adenosyl-l-methionine, enhances IkappaB-alpha expression. SL-HPR prevented these changes and induced a decrease in expression of iNos, c-myc, cyclin D1 and Vegf-A genes, that were over-expressed in preneoplastic liver and nodules, and a decrease in Bcl-2/Bax, Bcl-2/Bad and Bcl-xL/Bax mRNA ratios with respect to the lesions of control rats. Liposomes alone did not influence the parameters tested. These results indicate that signal transduction pathways controlled by NF-kappaB, nitric oxide and S-adenosyl-l-methionine are deregulated in pre-cancerous lesions. Recovery from these alterations by SL-HPR is associated with chemoprevention of hepatocarcinogenesis. Overall, these studies elucidate some molecular changes, in early stages of hepatocarcinogenesis, and underline their pathogenetic role. Moreover, they demonstrate a partially new mechanism of HPR chemopreventive effect and indicate the potential clinical relevance of this compound for prevention of hepatocellular carcinoma.
Simile
Maria M
MM
Department of Biomedical Sciences, Division of Experimental Pathology and Oncology, University of Sassari, Italy.
Pagnan
Gabriella
G
Pastorino
Fabio
F
Brignole
Chiara
C
De Miglio
Maria R
MR
Muroni
Maria R
MR
Asara
Giuseppina
G
Frau
Maddalena
M
Seddaiu
Maria A
MA
Calvisi
Diego F
DF
Feo
Francesco
F
Ponzoni
Mirco
M
Pascale
Rosa M
RM
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D019938:Cyclin D1 / Q000378:metabolism; D017313:Fenretinide / Q000008:administration & dosage / Q000494:pharmacology*; D020672:I-kappa B Proteins / Q000378:metabolism*; D008081:Liposomes / Q000008:administration & dosage; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008716:Methionine Adenosyltransferase / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D012436:S-Adenosylmethionine / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
D000970:Antineoplastic Agents; D019938:Cyclin D1; D017313:Fenretinide; D020672:I-kappa B Proteins; D008081:Liposomes; D008716:Methionine Adenosyltransferase; D000072000:NF-KappaB Inhibitor alpha; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D017346:Protein Serine-Threonine Kinases; D016271:Proto-Oncogene Proteins c-myc; D012436:S-Adenosylmethionine; D042461:Vascular Endothelial Growth Factor A; D000097782:NF-kappaB-Inducing Kinase; C000606206:Nfkbia protein, rat; C496318:Nos2 protein, rat