Open Access

Human bladder cancer cells undergo cisplatin-induced apoptosis that is associated with p53-dependent and p53-independent responses

  • Authors:
    • Eumorphia G. Konstantakou
    • Gerassimos E. Voutsinas
    • Panagiotis K. Karkoulis
    • Gerasimos Aravantinos
    • Lukas H. Margaritis
    • Dimitrios J. Stravopodis
  • View Affiliations

  • Published online on: August 1, 2009     https://doi.org/10.3892/ijo_00000353
  • Pages: 401-416
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Abstract

Cisplatin is a first-line chemotherapeutic agent and a powerful component of standard treatment regimens for several human malignancies including bladder cancer. DNA-Pt adducts produced by cisplatin are mainly responsible for cellular toxicity and induction of apoptosis. Identification of the mechanisms that control sensitivity to cisplatin is central to improving its therapeutic index and to successfully encountering the acquired resistance frequently emerging during therapy. In the present study, using MTT-based assays, Western blotting and semi-quantitative RT-PCR, we examined the apoptosis-related cellular responses to cisplatin exposure in two human urinary bladder cancer cell lines characterized by different malignancy grade and p53 genetic status. Both RT4 (grade I; wild-type p53) and T24 (grade III; mutant p53) cell types proved to be vulnerable to cisplatin apoptotic activity, albeit in a grade-dependent and drug dose-specific manner, as demonstrated by the proteolytic processing profiles of Caspase-8, Caspase-9, Caspase-3, and the Caspase repertoire characteristic substrates PARP and Lamin A/C, as well. The differential resistance of RT4 and T24 cells to cisplatin-induced apoptosis was associated with an RT4-specific phosphorylation (Ser15; Ser392) pattern of p53, together with structural amputations of the Akt and XIAP anti-apoptotic regulators. Furthermore, cisplatin administration resulted in a Granzyme B-mediated proteolytic cleavage of Hsp90 molecular chaperone, exclusively occurring in RT4 cells. To generate functional networks, expression analysis of a number of genes, including Bik, Bim, Bcl-2, FAP-1, Fas, FasL, TRAIL, Puma, Caspase-10, ATP7A, ATP7B and MRP1, was performed, strongly supporting the role of p53-dependent and p53-independent transcriptional responses in cisplatin-induced apoptosis of bladder cancer cells.

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August 2009
Volume 35 Issue 2

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Konstantakou EG, Voutsinas GE, Karkoulis PK, Aravantinos G, Margaritis LH and Stravopodis DJ: Human bladder cancer cells undergo cisplatin-induced apoptosis that is associated with p53-dependent and p53-independent responses. Int J Oncol 35: 401-416, 2009
APA
Konstantakou, E.G., Voutsinas, G.E., Karkoulis, P.K., Aravantinos, G., Margaritis, L.H., & Stravopodis, D.J. (2009). Human bladder cancer cells undergo cisplatin-induced apoptosis that is associated with p53-dependent and p53-independent responses. International Journal of Oncology, 35, 401-416. https://doi.org/10.3892/ijo_00000353
MLA
Konstantakou, E. G., Voutsinas, G. E., Karkoulis, P. K., Aravantinos, G., Margaritis, L. H., Stravopodis, D. J."Human bladder cancer cells undergo cisplatin-induced apoptosis that is associated with p53-dependent and p53-independent responses". International Journal of Oncology 35.2 (2009): 401-416.
Chicago
Konstantakou, E. G., Voutsinas, G. E., Karkoulis, P. K., Aravantinos, G., Margaritis, L. H., Stravopodis, D. J."Human bladder cancer cells undergo cisplatin-induced apoptosis that is associated with p53-dependent and p53-independent responses". International Journal of Oncology 35, no. 2 (2009): 401-416. https://doi.org/10.3892/ijo_00000353