title: Vitamin E metabolite 13'-carboxychromanols inhibit pro-inflammatory enzymes, induce apoptosis and autophagy in human cancer cells by modulating sphingolipids and suppress colon tumor development in mice.
abstract: Vitamin E forms are substantially metabolized to various carboxychromanols including 13'-carboxychromanols (13'-COOHs) that are found at high levels in feces. However, there is limited knowledge about functions of these metabolites. Here we studied δT-13'-COOH and δTE-13'-COOH, which are metabolites of δ-tocopherol and δ-tocotrienol, respectively. δTE-13'-COOH is also a natural constituent of a traditional medicine Garcinia Kola. Both 13'-COOHs are much stronger than tocopherols in inhibition of pro-inflammatory and cancer promoting cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX), and in induction of apoptosis and autophagy in colon cancer cells. The anticancer effects by 13'-COOHs appeared to be partially independent of inhibition of COX-2/5-LOX. Using liquid chromatography tandem mass spectrometry, we found that 13'-COOHs increased intracellular dihydrosphingosine and dihydroceramides after short-time incubation in HCT-116 cells, and enhanced ceramides while decreased sphingomyelins during prolonged treatment. Modulation of sphingolipids by 13'-COOHs was observed prior to or coinciding with biochemical manifestation of cell death. Pharmaceutically blocking the increase of these sphingolipids partially counteracted 13'-COOH-induced cell death. Further, 13'-COOH inhibited dihydroceramide desaturase without affecting the protein expression. In agreement with these mechanistic findings, δTE-13'-COOH significantly suppressed the growth and multiplicity of colon tumor in mice. Our study demonstrates that 13'-COOHs have anti-inflammatory and anticancer activities, may contribute to in vivo anticancer effect of vitamin E forms and are promising novel cancer prevention agents.
authors.affiliation: Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Jang
authors.affiliation: Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Na-Young
authors.initials: NY
authors.lastname: Park
authors.affiliation: Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Agnetha Linn
authors.initials: AL
authors.lastname: Rostgaard-Hansen
authors.affiliation: Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Jianjie
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA. Electronic address: qjiang@purdue.edu.
authors.forename: Qing
authors.initials: Q
authors.lastname: Jiang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics*; D001343:Autophagy / Q000187:drug effects; D002839:Chromans / Q000008:administration & dosage; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000235:genetics*; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage; D029763:Garcinia kola / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D013107:Sphingolipids / Q000378:metabolism; D024505:Tocopherols / Q000378:metabolism; D014810:Vitamin E / Q000378:metabolism*
chemical_list: D002839:Chromans; D052246:Cyclooxygenase 2 Inhibitors; D013107:Sphingolipids; D014810:Vitamin E; C029141:2,2,5,7,8-pentamethyl-1-hydroxychroman; D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C583212:ALOX5 protein, human; D024505:Tocopherols
keywords: Apoptosis; Autophagy; Cancer; Sphingolipid; Vitamin E metabolites