Sphingosine kinase 1 inhibition sensitizes hormone-resistant prostate cancer to docetaxel

Lysann Sauer, Joao Nunes, Vishal Salunkhe, Lenka Skalska, Takafumi Kohama, Olivier Cuvillier, Jonathan Waxman, Dmitry Pchejetski

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)

Abstract

It has recently been shown that docetaxel chemotherapy is effective in prolonging life in patients with prostate cancer (PCa). We have investigated potential ways of increasing the effectiveness of chemotherapy in this disease. We have previously reported that sphingosine kinase 1 (SphK1) inhibition is a key step in docetaxel-induced apoptosis in the PC-3 PCa cell line and that pharmacologicalSphK1 inhibition is chemosensitizing in the docetaxel-resistant PCa LNCaP cell line. In this study we have addressed the mechanism of docetaxel-induced apoptosis of PC-3 cells and identified SphK1-dependent and -independent components. We have shown that SphK1 inhibition by docetaxel is a two-step process involving an initial loss of enzyme activity followed by a decrease in SphK1 gene expression. Using hormoneresistant PC-3 and DU145 PCa cells we have demonstrated that both pharmacological and siRNA-mediated SphK1 inhibition leads to a four-fold decrease in the docetaxel IC50 dose. This work points out to potential ways of increasing the effectiveness of chemotherapy for PCa by SphK1 inhibition.
Original languageEnglish
Pages (from-to)2728-36
Number of pages9
JournalInternational Journal of Cancer
Volume125
Issue number11
DOIs
Publication statusPublished - 1 Dec 2009

Keywords

  • Antineoplastic Agents
  • Apoptosis
  • Blotting, Western
  • Caspases
  • Cell Cycle
  • Cell Line, Tumor
  • Cell Proliferation
  • Drug Resistance, Neoplasm
  • Flow Cytometry
  • Humans
  • Male
  • Neoplasms, Hormone-Dependent
  • Phosphotransferases (Alcohol Group Acceptor)
  • Prostatic Neoplasms
  • RNA, Messenger
  • RNA, Small Interfering
  • Reverse Transcriptase Polymerase Chain Reaction
  • Taxoids

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