15-hydroxy-5-8-11-13-eicosatetraenoic-acid and Colorectal-Neoplasms

Butyrate, a short-chain fatty acid, modulates proliferation and differentiation of normal and neoplastic colonocytes. We examined the expression of 5-lipoxygenase (5-LO) and its metabolites in human colorectal carcinoma (Caco-2) cells, exposed to differentiation-inducing doses of butyrate. Treatment with butyrate significantly increased 5-lipoxygenase mRNA and protein in comparison to nontreated cells. Cyclooxygenases (COX)-1 and COX-2 mRNA were not significantly influenced by the treatment. However, 5-LO activity, low in nontreated cells, increased only minimally after butyrate, and its metabolic product (5-HETE) was detectable neither in control nor in treated cells. In contrast, 15-HETE (a product of 15-LO, which is also upregulated by butyrate) rose significantly. We conclude that, although being overexpressed by butyrate on mRNA and protein level, 5-LO remains inactive in differentiating Caco-2 cells. This is likely to be due either to some associated actions of butyrate, or to 5-LO-inhibition by 15-HETE, concomitantly induced by butyrate treatment.

Topics: 5-Lipoxygenase-Activating Proteins; Arachidonate 5-Lipoxygenase; Butyric Acid; Caco-2 Cells; Carrier Proteins; Cell Differentiation; Cell Division; Colorectal Neoplasms; Cyclooxygenase Inhibitors; Humans; Hydroxyeicosatetraenoic Acids; Lipoxygenase Inhibitors; Membrane Proteins; RNA, Messenger; RNA, Neoplasm; Transforming Growth Factor beta; Up-Regulation

The gamma isoform of the peroxisome proliferator-activated receptor, PPAR gamma, regulates adipocyte differentiation and has recently been shown to be expressed in neoplasia of the colon and other tissues. We have found four somatic PPAR gamma mutations among 55 sporadic colon cancers: one nonsense, one frameshift, and two missense mutations. Each greatly impaired the function of the protein. c.472delA results in deletion of the entire ligand binding domain. Q286P and K319X retain a total or partial ligand binding domain but lose the ability to activate transcription through a failure to bind to ligands. R288H showed a normal response to synthetic ligands but greatly decreased transcription and binding when exposed to natural ligands. These data indicate that colon cancer in humans is associated with loss-of-function mutations in PPAR gamma.

Topics: Amino Acid Substitution; Binding Sites; Chromans; Colorectal Neoplasms; Dimerization; DNA-Binding Proteins; Exons; Genes, Tumor Suppressor; Humans; Hydroxyeicosatetraenoic Acids; Ligands; Linoleic Acids; Linoleic Acids, Conjugated; Mutation; Prostaglandin D2; Protein Binding; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Response Elements; Retinoid X Receptors; Rosiglitazone; Thiazoles; Thiazolidinediones; Transcription Factors; Transcriptional Activation; Troglitazone