Short-chain ceramides depress integrin cell surface expression and function in colorectal cancer cells

Cancer Lett. 2016 Jul 1;376(2):199-204. doi: 10.1016/j.canlet.2016.03.049. Epub 2016 Apr 1.

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.

Keywords: C6-ceramide; Cell migration; Ceramide; Colorectal cancer; Integrin; Sphingolipids.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Neoplasm / metabolism
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Adhesion / drug effects*
  • Cell Movement / drug effects*
  • Cell Survival / drug effects
  • Ceramides / chemistry
  • Ceramides / pharmacology*
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Drug Compounding
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Integrin beta1 / metabolism
  • Integrin beta4 / metabolism
  • Integrins / metabolism*
  • Molecular Structure
  • Neoplasm Metastasis
  • Signal Transduction / drug effects
  • Time Factors

Substances

  • Antigens, Neoplasm
  • Antineoplastic Agents
  • Ceramides
  • ITGB4 protein, human
  • Integrin beta1
  • Integrin beta4
  • Integrins
  • integrin alphavbeta6
  • N-caproylsphingosine