Thymidine phosphorylase suppresses apoptosis induced by microtubule-interfering agents

Biochem Pharmacol. 2005 Jul 1;70(1):13-21. doi: 10.1016/j.bcp.2005.04.017.

Abstract

We investigated the ability of thymidine phosphorylase (TP) to confer cancer cells resistance to MIA (microtubule-interfering agents)-induced apoptosis. Jurkat cells were stably transfected with TP cDNA (Jurkat/TP) and the sensitivity to MIAs were examined. Jurkat/TP cells were more resistant to apoptosis induced by nocodazole, vincristine, vinblastine, paclitaxel and 2-methoxyestradiol than mock-transfected Jurkat/CV cells. TP enzymatic activity was not required for this effect of TP. Jurkat/TP cells showed weak phosphorylation of Bcl-2, and kinase inhibitors staurosporine and genistein attenuated not only MIA-induced Bcl-2 phosphorylation but also cytotoxicity of MIA in Jurkat/CV, but not in Jurkat/TP. MIAs diminished expression of FasL in Jurkat/TP but not in Jurkat/CV, and neutralization of FasL by anti-FasL antibody considerably attenuated the cytotoxic effect of the MIAs in Jurkat/CV, but the effect of the antibody was marginal in Jurkat/TP cells. Our study provides further evidence that TP functions in conferring resistance on cancer cells to the stress induced by MIAs. In addition, we show that TP-induced inhibition of Bcl-2 phosphorylation and suppression of FasL may contribute to the protective function of TP in cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Cell Line, Tumor
  • Cytoprotection
  • Fas Ligand Protein
  • Humans
  • Membrane Glycoproteins / analysis
  • Membrane Glycoproteins / antagonists & inhibitors
  • Microtubules / drug effects*
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Thymidine Phosphorylase / physiology*

Substances

  • FASLG protein, human
  • Fas Ligand Protein
  • Membrane Glycoproteins
  • Proto-Oncogene Proteins c-bcl-2
  • Thymidine Phosphorylase
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3