Targeting sphingosine kinase-1 to inhibit melanoma

Pigment Cell Melanoma Res. 2012 Mar;25(2):259-74. doi: 10.1111/j.1755-148X.2012.00970.x.

Abstract

Resistance to therapies develops rapidly for melanoma leading to more aggressive disease. Therefore, agents are needed that specifically inhibit proteins or pathways controlling the development of this disease, which can be combined, dependent on genes deregulated in a particular patient's tumors. This study shows that elevated sphingosine-1-phosphate (S-1-P) levels resulting from increased activity of sphingosine kinase-1 (SPHK1) occur in advanced melanomas. Targeting SPHK1 using siRNA decreased anchorage-dependent and -independent growth as well as sensitized melanoma cells to apoptosis-inducing agents. Pharmacological SPHK1 inhibitors SKI-I but not SKI-II decreased S-1-P content, elevated ceramide levels, caused a G2-M block and induced apoptotic cell death in melanomas. Targeting SPHK1 using siRNA or the pharmacological agent called SKI-I decreased the levels of pAKT. Furthermore, SKI-I inhibited the expression of CYCLIN D1 protein and increased the activity of caspase-3/7, which in turn led to the degradation of PARP. In animals, SKI-I but not SKI-II retarded melanoma growth by 25-40%. Thus, targeting SPHK1 using siRNAs or SKI-I has therapeutic potential for melanoma treatment either alone or in combination with other targeted agents.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Adhesion / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cyclin D1 / metabolism
  • Down-Regulation / drug effects
  • Fibroblasts / drug effects
  • Fibroblasts / pathology
  • G1 Phase Cell Cycle Checkpoints / drug effects
  • Humans
  • Lysophospholipids / metabolism
  • Melanocytes / drug effects
  • Melanocytes / pathology
  • Melanoma / drug therapy*
  • Melanoma / enzymology
  • Melanoma / pathology*
  • Mice
  • Molecular Targeted Therapy*
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use*
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Small Interfering / metabolism
  • Resting Phase, Cell Cycle / drug effects
  • Skin Neoplasms / drug therapy
  • Skin Neoplasms / enzymology
  • Skin Neoplasms / pathology
  • Sphingosine / analogs & derivatives
  • Sphingosine / metabolism
  • Staurosporine / pharmacology
  • Thiazoles / pharmacology
  • Up-Regulation / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • 4-(4-(4-chloro-phenyl)thiazol-2-ylamino)phenol
  • CCND1 protein, human
  • Lysophospholipids
  • Protein Kinase Inhibitors
  • RNA, Small Interfering
  • Thiazoles
  • Cyclin D1
  • sphingosine 1-phosphate
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • Proto-Oncogene Proteins c-akt
  • Staurosporine
  • Sphingosine