Sphingosine kinase-1 as a chemotherapy sensor in prostate adenocarcinoma cell and mouse models

Dmitry Pchejetski, Muriel Golzio, Elisabeth Bonhoure, Cyril Calvet, Nicolas Doumerc, Virginie Garcia, Catherine Mazerolles, Pascal Rischmann, Justin Teissié, Bernard Malavaud, Olivier Cuvillier

Research output: Contribution to journalArticle

175 Citations (Scopus)

Abstract

Systemic chemotherapy was considered of modest efficacy in prostate cancer until the recent introduction of taxanes. We took advantage of the known differential effect of camptothecin and docetaxel on human PC-3 and LNCaP prostate cancer cells to determine their effect on sphingosine kinase-1 (SphK1) activity and subsequent ceramide/sphingosine 1-phosphate (S1P) balance in relation with cell survival. In vitro, docetaxel and camptothecin induced strong inhibition of SphK1 and elevation of the ceramide/S1P ratio only in cell lines sensitive to these drugs. SphK1 overexpression in both cell lines impaired the efficacy of chemotherapy by decreasing the ceramide/S1P ratio. Alternatively, silencing SphK1 by RNA interference or pharmacologic inhibition induced apoptosis coupled with ceramide elevation and loss of S1P. The differential effect of both chemotherapeutics was confirmed in an orthotopic PC-3/green fluorescent protein model established in nude mice. Docetaxel induced a stronger SphK1 inhibition and ceramide/S1P ratio elevation than camptothecin. This was accompanied by a smaller tumor volume and the reduced occurrence and number of metastases. SphK1-overexpressing PC-3 cells implanted in animals developed remarkably larger tumors and resistance to docetaxel treatment. These results provide the first in vivo demonstration of SphK1 as a sensor of chemotherapy.
Original languageEnglish
Pages (from-to)11667-75
Number of pages9
JournalCancer Research
Volume65
Issue number24
DOIs
Publication statusPublished - 15 Dec 2005

Keywords

  • Adenocarcinoma
  • Animals
  • Antineoplastic Agents, Phytogenic
  • Apoptosis
  • Blotting, Western
  • Camptothecin
  • Ceramides
  • Disease Models, Animal
  • Flow Cytometry
  • Green Fluorescent Proteins
  • Humans
  • Lysophospholipids
  • Male
  • Mice
  • Mice, Nude
  • Microscopy, Fluorescence
  • Neoplasm Recurrence, Local
  • Neoplasms, Hormone-Dependent
  • Phosphotransferases (Alcohol Group Acceptor)
  • Prostatic Neoplasms
  • RNA Interference
  • Sphingosine
  • Taxoids
  • Tumor Cells, Cultured

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