Effect of vitamin E on gene expression changes in diet-related carcinogenesis.
Colorectal cancer (CRC) is responsible for the second highest associated mortality in Western Europe and the United States. Approximately 95% of CRC is sporadic and believed to involve environmental agents and chronic inflammation as causal elements. Several recent studies have suggested a link with diet, in particular, red meat, dietary fats, and low consumption of vegetables. Lipid peroxidation and arachidonic acid metabolism have specifically been implicated in genotoxicity, tumor initiation, and promotion. We have examined the global gene expression profiles (Affymetrix; HU133A) of differentiated vs. undifferentiated colonocytes (CRL-1807), with and without vitamin E supplementation, while undergoing a lipid peroxidative stress. Malondialdehyde and hydroxynonenal, generated by heating a mixture of linoleic and linolenic acid, caused DNA adduct formation identified by immunofluoresence. We also observed a decreased ability for vitamin E to upregulate detoxifying enzymes against free-radical peroxidation, with the exception of mitochondrial superoxide dismutase in undifferentiated cells. However, there was an increased ability in undifferentiated, rather than in differentiated, colonic cells to detect DNA damage, initiate cytostasis, and then effect subsequent DNA repair and apoptosis, in the presence of vitamin E. The expression profile implies less genotoxic stress is experienced in vitamin E-supplemented colonocytes, particularly undifferentiated cells, and points to a mechanism by which dietary supplementation may prevent genotoxic damage and subsequent carcinogenic events in the colon, by both antioxidant and non-antioxidant-related mechanisms.
Lunec
Joseph
J
Genome Instability Group, University of Leicester, Genome Instability Group, Department of Cancer & Molecular Medicine, Level 0, RKCSB, LRI, Leicester, LE2 7LX, UK. jl20@le.ac.uk
Halligan
Eugene
E
Mistry
Nalini
N
Karakoula
Katherine
K
D016588:Anticarcinogenic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D016718:Arachidonic Acid / Q000378:metabolism; D003110:Colonic Neoplasms / Q000209:etiology* / Q000235:genetics*; D018736:DNA Adducts / Q000032:analysis; D004032:Diet; D019587:Dietary Supplements; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D006801:Humans; D015227:Lipid Peroxidation; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis; D014407:Tumor Cells, Cultured; D014810:Vitamin E / Q000494:pharmacology*
D016588:Anticarcinogenic Agents; D000975:Antioxidants; D018736:DNA Adducts; D012333:RNA, Messenger; D014810:Vitamin E; D016718:Arachidonic Acid