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Thymidylate Synthase Inhibition Induces p53-dependent and p53-independent Apoptotic Responses in Human Urinary Bladder Cancer Cells

Thymidylate Synthase Inhibition Induces p53-dependent and p53-independent Apoptotic Responses in Human Urinary Bladder Cancer Cells

Dimitrios J Stravopodis, Panagiotis K Karkoulis, Eumorphia G Konstantakou, Sophia Melachroinou, Angeliki Thanasopoulou, Gerasimos Aravantinos, Lukas H Margaritis, Ema Anastasiadou, Gerassimos E Voutsinas

J Cancer Res Clin Oncol. 2011 Feb;137(2):359-74.

PMID: 20425122

Abstract:

Purpose:
In search for more effective clinical protocols, the antimetabolite drug 5-fluorouracil (5-FU) has been successfully included in new regimens of bladder cancer combination chemotherapy. In the present study, we have investigated the effects of 5-FU treatment on apoptosis induction in wild-type and mutant p53 urinary bladder cancer cells.
Methods:
We have used MTT-based assays, FACS analysis, Western blotting and semi-quantitative RT-PCR in RT4 and RT112 (grade I, wild-type p53), as well as in T24 (grade III, mutant p53) and TCCSUP (grade IV, mutant p53) human urinary bladder cancer cell lines.
Results:
In the urothelial bladder cancer cell lines RT4 and T24, 5-FU-induced TS inhibition proved to be associated with cell type-dependent (a) sensitivity to the drug, (b) Caspase-mediated apoptosis, (c) p53 stabilization and activation, as well as Rb phosphorylation and E2F1 expression and (d) transcriptional regulation of p53 target genes and their cognate proteins, while an E2F-dependent transcriptional network did not seem to be critically engaged in such type of responses.
Conclusions:
We have shown that in the wild-type p53 context of RT4 cells, 5-FU-triggered apoptosis was prominently efficient and mainly regulated by p53-dependent mechanisms, whereas the mutant p53 environment of T24 cells was able to provide notable levels of resistance to apoptosis, basically ascribed to E2F-independent, and still unidentified, pathways. Nevertheless, the differential vulnerability of RT4 and T24 cells to 5-FU administration could also be associated with cell-type-specific transcriptional expression patterns of certain genes critically involved in 5-FU metabolism.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4248145	p53 human			Price

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