DDP-induced cytotoxicity is not influenced by p53 in nine human ovarian cancer cell lines with different p53 status

Feudis, P. De; Debernardis, Domizia; Beccaglia, Patrizia; Valenti, Monica; Siré, E G; Arzani, Dario; Stanzione, Sabrina; Parodi, Silvio; D’Incalci, Maurizio; Russo, Patrizia; Broggini, Massimo

doi:10.1038/bjc.1997.412

Cited by 62 publications

(43 citation statements)

References 21 publications

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“…31,32 We found a strong correlation between the expression of p53 and the sensitivity to cisplatin-induced apoptosis. Caov-4 cells responded to cisplatin treatment by elevated p53 expression followed by Bid cleavage and Bax activation (Supplementary Figure S1B and C).…”

Section: Discussionmentioning

confidence: 78%

DNA damage induces two distinct modes of cell death in ovarian carcinomas

et al. 2007

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Activation of p53 by cellular stress may lead to either cell cycle arrest or apoptotic cell death. Restrictions in a cell's ability to halt the cell cycle might, in turn, cause mitotic catastrophe, a delayed type of cell death with distinct morphological features. Here, we have investigated the contribution of p53 and caspase-2 to apoptotic cell death and mitotic catastrophe in cisplatin-treated ovarian carcinoma cell lines. We report that both functional p53 and caspase-2 were required for the apoptotic response, which was preceded by translocation of nuclear caspase-2 to the cytoplasm. In the absence of functional p53, cisplatin treatment resulted in caspase-2-independent mitotic catastrophe followed by necrosis. In these cells, apoptotic functions could be restored by transient expression of wt p53. Hence, p53 appeared to act as a switch between apoptosis and mitotic catastrophe followed by necrosis-like lysis in this experimental model. Further, we show that inhibition of Chk2, and/or 14-3-3r deficiency, sensitized cells to undergo mitotic catastrophe upon treatment with DNA-damaging agents. However, apoptotic cell death seemed to be the final outcome of this process. Thus, we hypothesize that the final mode of cell death triggered by DNA damage in ovarian carcinoma cells is determined by the profile of proteins involved in the regulation of the cell cycle, such as p53-and Chk2-related proteins.

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Section: Discussionmentioning

confidence: 78%

DNA damage induces two distinct modes of cell death in ovarian carcinomas

et al. 2007

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“…However, the relevance of p53 to the development of cisplatin resistance in cancer remains unclear. Indeed, in vitro experiments, as well as the study of p53 status in various sensitive and resistant tumors have yielded conflicting data (Brown et al, 1993;Eliopoulos et al, 1995;Herod et al, 1996;Wu and El-Deiry, 1996;De Feudis et al, 1997;O'Connor et al, 1997;Pestell et al, 1998Pestell et al, , 2000.…”

Section: Introductionmentioning

confidence: 99%

Gene expression response to cisplatin treatment in drug-sensitive and drug-resistant ovarian cancer cells

Wood

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et al. 2006

Oncogene

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“…in ovarian carcinomas (Kupryjańczyk et al, 1993;Casey et al, 1996;DiCioccio et al, 1998;Wen et al, 1999), studies on TP53 status and tumour response to cisplatin-based chemotherapy have not so far given equivocal results (Righetti et al, 1996;de Feudis et al, 1997;Baekelandt et al, 1999;Eisenhauer et al, 1999;Fallows et al, 2001;Reles et al, 2001).…”

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confidence: 99%

Evaluation of clinical significance of TP53, BCL-2, BAX and MEK1 expression in 229 ovarian carcinomas treated with platinum-based regimen

et al. 2003

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In cell line studies, BCL-2, BAX, as well as novel MEK1 protein levels have strong influence on ovarian cancer response to cisplatinbased chemotherapy. However, such associations have not been demonstrated clinically. We evaluated prognostic/predictive significance of these proteins with regard to TP53 status. Immunohistochemical analysis was performed on 229 ovarian carcinomas FIGO stage IIB -IV treated with platinum-based chemotherapy; the results were analysed by the Cox and logistic regression models. Clinical parameters (residual tumour size, patient age, FIGO stage) were the only indicators of overall survival (OS) and the strongest predictors of complete remission (CR). On the other hand, BAX expression was the strongest (P ¼ 0.005) or the only (in FIGO IIIC, P ¼ 0.02) prognostic indicator of disease-free survival (DFS) in the TP53(+) group. TP53(+) and TP53(À) ovarian carcinomas differed in clinical and molecular prognostic and predictive factors. Another novel finding is that CR was negatively influenced by high BAX expression in all patients group (P ¼ 0.047) and by BCL2 expression in the TP53(À) group (P ¼ 0.05). High MEK1 expression was associated with endometrioid and clear cell carcinomas (P ¼ 0.049); its loss was found with advancing FIGO stage (P ¼ 0.002). Our results suggest that binomial TP53 status divides ovarian carcinomas into two biologically distinct groups. BAX expression is an important factor of DFS in the TP53(+) group. BCL-2 and BAX, but not MEK1 expressions have predictive value in ovarian cancer patients treated with platinum-based chemotherapy.

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DDP-induced cytotoxicity is not influenced by p53 in nine human ovarian cancer cell lines with different p53 status

Cited by 62 publications

References 21 publications

DNA damage induces two distinct modes of cell death in ovarian carcinomas

DNA damage induces two distinct modes of cell death in ovarian carcinomas

Gene expression response to cisplatin treatment in drug-sensitive and drug-resistant ovarian cancer cells

Evaluation of clinical significance of TP53, BCL-2, BAX and MEK1 expression in 229 ovarian carcinomas treated with platinum-based regimen

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