Inhibition of Ceramide Glucosylation Sensitizes Lung Cancer Cells to ABC294640, a First-In-Class Small Molecule SphK2 Inhibitor

Biochem Biophys Res Commun. 2016 Aug 5;476(4):230-236. doi: 10.1016/j.bbrc.2016.05.102. Epub 2016 May 21.

Abstract

Sphingosine kinase 2 (SphK2) is proposed as a novel oncotarget for lung cancer. Here, we studied the anti-lung cancer cell activity by ABC294640, a first-in-class SphK2 inhibitor. We showed that ABC294640 suppressed growth of primary and A549 human lung cancer cells, but sparing SphK2-low lung epithelial cells. Inhibition of SphK2 by ABC294640 increased ceramide accumulation, but decreased pro-survival sphingosine-1-phosphate (S1P) content, leading to lung cancer cell apoptosis activation. Significantly, we show that glucosylceramide synthase (GCS) might be a major resistance factor of ABC294640. The GCS inhibitor 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) or GCS shRNA/siRNA knockdown facilitated ABC294640-induced ceramide production and lung cancer cell apoptosis. Reversely, forced overexpression of GCS reduced ABC294640's sensitivity, resulting in decreased ceramide accumulation and apoptosis induction in A549 cells. These findings provide further evidences to support that targeting SphK2 by ABC294640 may be a rational treatment option for lung cancer. Ceramide glucosylation inhibition may further sensitize lung cancer cells to ABC294640.

Keywords: ABC294640; Ceramide; Glucosylceramide synthase (GCS); Lung cancer; Sphingosine kinase 2 (SphK2).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Adamantane / analogs & derivatives*
  • Adamantane / pharmacology
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Proliferation / drug effects
  • Ceramides / metabolism*
  • Drug Resistance, Neoplasm
  • Glucosyltransferases / antagonists & inhibitors*
  • Glucosyltransferases / metabolism
  • Humans
  • Lung / drug effects
  • Lung / metabolism
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Pyridines / pharmacology*

Substances

  • Antineoplastic Agents
  • Ceramides
  • Pyridines
  • 3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide
  • Glucosyltransferases
  • ceramide glucosyltransferase
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase 2, human
  • Adamantane