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Thymidine phosphorylase suppresses apoptosis induced by microtubule-interfering agents

Hei-Cheul Jeung1, Xiao-Fang Che, Misako Haraguchi

  • 1Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan.

Biochemical Pharmacology
|May 24, 2005
PubMed

Insights

Thymidine phosphorylase (TP) enhances cancer cell resistance to microtubule-interfering agents (MIAs). TP inhibits Bcl-2 phosphorylation and FasL expression, contributing to MIA resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Microtubule-interfering agents (MIAs) are a class of chemotherapy drugs.
  • Cancer cells can develop resistance to apoptosis induced by MIAs.
  • Thymidine phosphorylase (TP) is an enzyme involved in nucleotide metabolism.

Purpose of the Study:

  • To investigate the role of thymidine phosphorylase (TP) in conferring resistance to MIA-induced apoptosis in cancer cells.
  • To elucidate the molecular mechanisms underlying TP-mediated resistance to MIAs.

Main Methods:

  • Stable transfection of Jurkat cells with TP cDNA (Jurkat/TP).
  • Assessment of apoptosis sensitivity to various MIAs (nocodazole, vincristine, vinblastine, paclitaxel, 2-methoxyestradiol).
  • Analysis of Bcl-2 phosphorylation, FasL expression, and effects of kinase inhibitors and anti-FasL antibodies.

Main Results:

  • Jurkat/TP cells exhibited increased resistance to MIA-induced apoptosis compared to control cells.
  • TP's enzymatic activity was not essential for this protective effect.
  • TP-expressing cells showed reduced Bcl-2 phosphorylation and diminished FasL expression upon MIA treatment.
  • Kinase inhibitors and FasL neutralization had differential effects on MIA cytotoxicity in Jurkat/TP versus control cells.

Conclusions:

  • TP confers resistance to MIA-induced apoptosis in cancer cells.
  • TP-mediated inhibition of Bcl-2 phosphorylation and suppression of FasL expression contribute to this protective function.
  • Targeting TP or its downstream pathways may offer strategies to overcome MIA resistance in cancer therapy.

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