Sphingosine kinase-1 is a downstream regulator of imatinib-induced apoptosis in chronic myeloid leukemia cells

Leukemia. 2008 May;22(5):971-9. doi: 10.1038/leu.2008.95. Epub 2008 Apr 10.

Abstract

We examined the involvement of sphingosine kinase-1 (SphK1), which governs the ceramide/sphingosine-1-phosphate balance, in susceptibility to imatinib of either sensitive or resistant chronic myeloid leukemia cells. Imatinib-sensitive LAMA84-s displayed marked SphK1 inhibition coupled with increased content of ceramide and decreased pro-survival sphingosine-1-phosphate. Conversely, no changes in the sphingolipid metabolism were observed in LAMA84-r treated with imatinib. Overcoming imatinib resistance in LAMA84-r with farnesyltransferase or MEK/ERK inhibitors as well as with cytosine arabinoside led to SphK1 inhibition. Overexpression of SphK1 in LAMA84-s cells impaired apoptosis and inhibited the effects of imatinib on caspase-3 activation, cytochrome c and Smac release from mitochondria through modulation of Bim, Bcl-xL and Mcl-1 expression. Pharmacological inhibition of SphK1 with F-12509a or its silencing by siRNA induced apoptosis of both imatinib-sensitive and -resistant cells, suggesting that SphK1 inhibition was critical for apoptosis signaling. We also show that imatinib-sensitive and -resistant primary cells from chronic myeloid leukemia patients can be successfully killed in vitro by the F-12509a inhibitor. These results uncover the involvement of SphK1 in regulating imatinib-induced apoptosis and establish that SphK1 is a downstream effector of the Bcr-Abl/Ras/ERK pathway inhibited by imatinib but upstream regulator of Bcl-2 family members.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis Regulatory Proteins
  • Apoptosis* / drug effects
  • Benzamides
  • Benzoquinones / pharmacology
  • Drug Resistance, Neoplasm
  • Fusion Proteins, bcr-abl / metabolism*
  • Humans
  • Imatinib Mesylate
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors
  • Phosphotransferases (Alcohol Group Acceptor) / physiology*
  • Piperazines / pharmacology*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Pyrimidines / pharmacology*
  • Signal Transduction

Substances

  • Apoptosis Regulatory Proteins
  • Benzamides
  • Benzoquinones
  • F 12509A
  • Piperazines
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrimidines
  • Imatinib Mesylate
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • Fusion Proteins, bcr-abl