Thymidine phosphorylase suppresses apoptosis induced by microtubule-interfering agents

• Published in: Biochemical pharmacology Vol. 70; no. 1; pp. 13 - 21
• Main Authors: Jeung, Hei-Cheul, Che, Xiao-Fang, Haraguchi, Misako, Furukawa, Tatsuhiko, Zheng, Chun-Lei, Sumizawa, Tomoyuki, Rha, Sun-Young, Roh, Jae Kyung, Akiyama, Shin-ichi
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.07.2005; Elsevier Science
• Subjects: Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Cell Line, Tumor; Cytoprotection; Experimental therapeutics; Fas Ligand Protein; Humans; Medical sciences; Membrane Glycoproteins - analysis; Membrane Glycoproteins - antagonists & inhibitors; Microtubule; Microtubules - drug effects; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Pharmacology. Drug treatments; Phosphorylation; Proto-Oncogene Proteins c-bcl-2 - metabolism; Thymidine phosphorylase; Thymidine Phosphorylase - physiology; Experimental therapeutics; Microtubule; Thymidine phosphorylase; Apoptosis; Treatment; Enzyme; Cell death; Transferases; Glycosyltransferases; Cytoskeleton; Pentosyltransferases
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2005.04.017

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-trasfected 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.