Article

Thymidine phosphorylase suppresses apoptosis induced by microtubule-interfering agents.

Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan.
Biochemical Pharmacology (impact factor: 4.7). 08/2005; 70(1):13-21. DOI:10.1016/j.bcp.2005.04.017 pp.13-21
Source: PubMed

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.

0 0
 · 
0 Bookmarks
 · 
24 Views
  • Source
    Article: The dual role of thymidine phosphorylase in cancer development and chemotherapy.
    Annelies Bronckaers, Federico Gago, Jan Balzarini, Sandra Liekens
    [show abstract] [hide abstract]
    ABSTRACT: Thymidine phosphorylase (TP), also known as "platelet-derived endothelial cell growth factor" (PD-ECGF), is an enzyme, which is upregulated in a wide variety of solid tumors including breast and colorectal cancers. TP promotes tumor growth and metastasis by preventing apoptosis and inducing angiogenesis. Elevated levels of TP are associated with tumor aggressiveness and poor prognosis. Therefore, TP inhibitors are synthesized in an attempt to prevent tumor angiogenesis and metastasis. TP is also indispensable for the activation of the extensively used 5-fluorouracil prodrug capecitabine, which is clinically used for the treatment of colon and breast cancer. Clinical trials that combine capecitabine with TP-inducing therapies (such as taxanes or radiotherapy) suggest that increasing TP expression is an adequate strategy to enhance the antitumoral efficacy of capecitabine. Thus, TP plays a dual role in cancer development and therapy: on the one hand, TP inhibitors can abrogate the tumorigenic and metastatic properties of TP; on the other, TP activity is necessary for the activation of several chemotherapeutic drugs. This duality illustrates the complexity of the role of TP in tumor progression and in the clinical response to fluoropyrimidine-based chemotherapy.
    Medicinal Research Reviews 06/2009; 29(6):903-53. · 10.70 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

anti-FasL antibody
 
apoptosis induced
 
Bcl-2 phosphorylation
 
cancer cells
 
cancer cells resistance
 
cytotoxic effect
 
genistein attenuated
 
Jurkat cells
 
Jurkat/TP
 
Jurkat/TP cells
 
kinase inhibitors staurosporine
 
microtubule-interfering agents)-induced apoptosis
 
mock-transfected Jurkat/CV cells
 
protective function
 
stress induced
 
TP cDNA
 
TP enzymatic activity
 
TP functions
 
TP-induced inhibition
 
weak phosphorylation