title: Short-chain ceramides depress integrin cell surface expression and function in colorectal cancer cells.
abstract: Colorectal cancer (CRC) is highly metastatic, significantly so to liver, a characteristic that embodies one of the most challenging aspects of treatment. The integrin family of cell-cell and cell-matrix adhesion receptors plays a central role in migration and invasion, functions that underlie metastatic potential. In the present work we sought to determine the impact of ceramide, which plays a key modulatory role in cancer suppression, on integrin cell surface expression and function in CRC cells in order to reveal possible ceramide-centric effects on tumor cell motility. Human CRC cells LoVo, HT-29, and HCT-116 were employed, which represent lines established from primary and metastatic sites. A cell-permeable, short-chain analog, C6-ceramide, was used as ceramide mimic. Exposure of cells to C6-ceramide (24 h) promoted a dose-dependent (2.5-10 µM) decrease in the expression of cell surface β1 and β4 integrin subunits in all cell lines; at 10 µM C6-ceramide, the decreases ranged from 30 to 50% of the control. Expression of cell surface αVβ6 integrin, which is associated with advanced invasion in CRC, was also suppressed by C6-ceramide. Decreases in integrin expression translated to diminished cellular adhesion, 50% of the control at 5 µM C6-ceramide, and markedly reduced cellular migration, approximately 30-40% of the control in all cell lines. Physicochemical examination revealed potent efficacy of nano-formulated C6-ceramide, but inferior activity of dihydro-C6-ceramide and L-C6-ceramide, compared to the unsaturated counterpart and the natural d-enantiomer, respectively. These studies demonstrate novel actions of ceramides that may have application in suppression of tumor metastasis, in addition to their known tumor suppressor effects.
authors.affiliation: Department of Biochemistry and Molecular Biology, Brody School of Medicine, East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27834, USA.
authors.forename: Samy A F
authors.initials: SA
authors.lastname: Morad
authors.affiliation: Department of Biochemistry and Molecular Biology, Brody School of Medicine, East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27834, USA.
authors.forename: Lance C
authors.initials: LC
authors.lastname: Bridges
authors.affiliation: Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
authors.forename: Alex D
authors.initials: AD
authors.lastname: Almeida Larrea
authors.affiliation: Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Mayen
authors.affiliation: Department of Biochemistry and Molecular Biology, Brody School of Medicine, East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27834, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: MacDougall
authors.affiliation: Department of Biochemistry and Molecular Biology, Brody School of Medicine, East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27834, USA.
authors.forename: Traci S
authors.initials: TS
authors.lastname: Davis
authors.affiliation: University of Virginia Cancer Center, Charlottesville, VA 22908-0716, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Kester
authors.affiliation: Department of Biochemistry and Molecular Biology, Brody School of Medicine, East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27834, USA. Electronic address: cabotm@ecu.edu.
authors.forename: Myles C
authors.initials: MC
authors.lastname: Cabot
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000737:chemistry / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004339:Drug Compounding; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D039663:Integrin beta4 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D015394:Molecular Structure; D009362:Neoplasm Metastasis; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D002518:Ceramides; C059834:ITGB4 protein, human; D019012:Integrin beta1; D039663:Integrin beta4; D016023:Integrins; C073878:integrin alphavbeta6; C101954:N-caproylsphingosine
keywords: C6-ceramide; Cell migration; Ceramide; Colorectal cancer; Integrin; Sphingolipids