title: Sphingosine Kinase 2 and Ceramide Transport as Key Targets of the Natural Flavonoid Luteolin to Induce Apoptosis in Colon Cancer Cells.
abstract: The plant flavonoid luteolin exhibits different biological effects, including anticancer properties. Little is known on the molecular mechanisms underlying its actions in colorectal cancer (CRC). Here we investigated the effects of luteolin on colon cancer cells, focusing on the balance between ceramide and sphingosine-1-phosphate (S1P), two sphingoid mediators with opposite roles on cell fate. Using cultured cells, we found that physiological concentrations of luteolin induce the elevation of ceramide, followed by apoptotic death of colon cancer cells, but not of differentiated enterocytes. Pulse studies revealed that luteolin inhibits ceramide anabolism to complex sphingolipids. Further experiments led us to demonstrate that luteolin induces an alteration of the endoplasmic reticulum (ER)-Golgi flow of ceramide, pivotal to its metabolic processing to complex sphingolipids. We report that luteolin exerts its action by inhibiting both Akt activation, and sphingosine kinase (SphK) 2, with the consequent reduction of S1P, an Akt stimulator. S1P administration protected colon cancer cells from luteolin-induced apoptosis, most likely by an intracellular, receptor-independent mechanism. Overall this study reveals for the first time that the dietary flavonoid luteolin exerts toxic effects on colon cancer cells by inhibiting both S1P biosynthesis and ceramide traffic, suggesting its dietary introduction/supplementation as a potential strategy to improve existing treatments in CRC.
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, LITA-Segrate, University of Milan, Milan, Italy.
authors.forename: Loubna
authors.initials: L
authors.lastname: Abdel Hadi
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, LITA-Segrate, University of Milan, Milan, Italy.
authors.forename: Clara
authors.initials: C
authors.lastname: Di Vito
authors.affiliation: Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico Milan, University of Milan, Milan, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Marfia
authors.affiliation: Department of Biomedical Sciences for Health, LITA-Segrate, University of Milan, Milan, Italy.
authors.forename: Anita
authors.initials: A
authors.lastname: Ferraretto
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, LITA-Segrate, University of Milan, Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Tringali
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, LITA-Segrate, University of Milan, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Viani
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, LITA-Segrate, University of Milan, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Riboni
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D002518:Ceramides / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D019610:Cytoprotection / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D020895:Enterocytes / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D047311:Luteolin / Q000494:pharmacology*; D008246:Lysophospholipids / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D002518:Ceramides; D047311:Luteolin; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate