Lack of correlation between cisplatin-induced apoptosis,p53 status and expression of Bcl-2 family proteins in testicular germ cell tumour cell lines

Burger, Herman; Nooter, Kees; Boersma, Antonius W. M.; Kortland, Christine J.; Stoter, G.

doi:10.1002/(sici)1097-0215(19971114)73:4<592::aid-ijc22>3.0.co;2-a

Cited by 92 publications

(76 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Most of the genes analysed, however, were either not detectable (no signal) or only weakly expressed in NCCIT cells (weak signals) and did not reveal any down-or upregulation after drug treatment. p53, the p53-regulated gene mdm-2 and genes from the Bcl-2 family belonged to this group, as reported by others (Burger et al, 1997;Kersemaekers et al, 2002) (Table 1). The expression level of five genes including IGFBP-2, AP-1, CDC25A, GADD45 and ID-1 was decreased in treated cells compared to the levels in untreated cells (Table 1).…”

Section: Analysis Of Apoptosis-regulating Genes Following Cddp Treatmentsupporting

confidence: 81%

“…The present study was focused on p53-independent mechanisms involved in CDDP-induced apoptosis of the human neoplastic germ cell line NCCIT, the p53 protein of which is known to remain inactive during the course of drug-induced apoptosis (Burger et al, 1997;Burger et al, 1999). To address this issue, we first studied dose-and time-dependent effects of CDDP on NCCIT cells.…”

Section: Discussionmentioning

confidence: 99%

“…Although Chresta et al (1996) postulated that a hypersensitivity of human TGCT to drug-dependent apoptosis may also be associated with functional p53 , Burger et al (1999) showed that abrogation of the p53 function does not affect the hypersensitivity of human TGCT cell lines to chemotherapy. Thus in human TGCT, apoptotic signalling pathways including those activated by CDDP seem to be -at least partly -p53 independent (Burger et al, 1997;Kersemaekers et al, 2002).…”

mentioning

confidence: 98%

See 2 more Smart Citations

Cisplatin-induced apoptosis in human malignant testicular germ cell lines depends on MEK/ERK activation

et al. 2004

View full text Add to dashboard Cite

Testicular germ cell tumours (TGCT) represent the most common malignancies in young males. Whereas in 1970s, the survival rate in patients with metastatic testicular tumours was only 5%, these days, 80% of the patients treated by modern chemotherapy will survive their disease. The drug that revolutionised the cure rate for patients with metastatic testicular tumours was cisdiamminedichloroplatinum (cisplatin, CDDP). In vitro experiments on neoplastic germ cell lines showed that their exquisite sensitivity to CDDP could be attributed to p53-dependent and -independent pathways. Applying cDNA macroarray, semiquantitative RT -PCR and Western blot analyses, blocking experiments, caspase activity assays, and morphological methods, we sought here to define the p53-independent pathway(s) involved in the CDDP-induced apoptosis. For this purpose, we used the human TGCT cell line NCCIT, the mutated p53 of which is known to remain inactive during the course of CDDP-induced apoptosis. Our experiments showed that within hours of CDDP application, two prototype members of the 'mitogen-activated protein kinase' (MAPK) family, designated 'MAPK ERK kinase' (MEK) and 'extracellular signal-regulated kinase' (ERK), were dually phosphorylated and caspase-3 became active. Functional assays using MEK inhibitors demonstrated that the phosphorylation of MEK and ERK was required for the activation of caspase-3 as the executing caspase. Interestingly, experiments with the human malignant germ cell line NTERA, which is known to possess wild-type p53, revealed the same results. Thus, our data suggest that CDDP mediates its p53-independent apoptosis-inducing effect on the malignant human testicular germ cells -at least partially -through activation of the MEK -ERK signalling pathway.

show abstract

Section: Analysis Of Apoptosis-regulating Genes Following Cddp Treatmentsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 98%

See 1 more Smart Citation

Cisplatin-induced apoptosis in human malignant testicular germ cell lines depends on MEK/ERK activation

et al. 2004

View full text Add to dashboard Cite

show abstract

“…In addition, a cell line expressing mutant p53 was derived from a cisplatinresistant human TGCT and exhibited relative resistance to cisplatin and reduced apoptotic cell death compared to a cell line expressing wild-type p53 that was derived from a sensitive TGCT (Houldsworth et al, 1998). In contrast, another panel of TGCT cell lines expressing either wild-type or mutant p53 did not confirm these results, since no relation between cisplatin sensitivity, apoptosis induction and p53 status was observed (Burger et al, 1997(Burger et al, , 1998a). An immunohistochemical study investigating p53 expression in drug-responsive and nonresponsive TGCT tumors indicated that p53 levels do not determine the sensitivity of TGCTs to chemotherapy (Kersemaekers et al, 2002a (Chresta et al, 1996;de Jong et al, 1999).…”

Section: Discussionmentioning

confidence: 96%

Low p21Waf1/Cip1 protein level sensitizes testicular germ cell tumor cells to Fas-mediated apoptosis

et al. 2004

View full text Add to dashboard Cite

In the present study, we investigated the relation between p21 expression and the sensitivity of testicular germ cell tumor (TGCT) cells to apoptotic stimuli. Despite similar cisplatin-induced wild-type p53 accumulation, the TGCT cell lines Tera and Scha expressed low p21 protein and mRNA levels in comparison to A2780 ovarian cancer cells. Inhibition of the proteasome complex with MG-132 increased p21 protein levels in TGCT cells but much more in A2780 cells, whereas cisplatin had no additional effect on p21 protein levels. Inhibition of caspase-3 activity in TGCT cells with the broad-spectrum caspase inhibitor zVAD-fmk had no effect on p21 levels and also not upon cisplatin treatment. A similar induction of p53 irradiation, in contrast to cisplatin, substantially increased both p21 mRNA and protein expression in Tera cells. Cisplatintreated Tera cells expressing low p21 protein levels were Fas-sensitive, while irradiation-induced p21, which was mainly localized in the cytosol, rendered irradiated Tera cells resistant to Fas-induced apoptosis. Sensitivity of irradiated Tera cells to Fas-induced apoptosis was restored by short interfering RNA-specific suppression of p21 expression. These results strongly indicate that the low p21 protein levels are caused by reduced p21 gene transcription and sensitize cisplatin-treated TGCT cells to the Fas death pathway.

show abstract

“…However, there have been reports of mechanisms not involving these members of the bcl-2 family of proteins in cisplatininduced apoptosis. [33][34][35] A resistance to cellular apoptosis could not be reproduced through pre-incubation with low concentrations of cisplatin. However, resistance to etoposide following pre-incubation with doxorubicin, another topo II inhibitor, was seen.…”

Section: Discussionmentioning

confidence: 99%

Exposure to low concentrations of etoposide reduces the apoptotic capability of leukaemic cell lines

2002

View full text Add to dashboard Cite

The use of topoisomerase inhibitors has been associated with the development of secondary malignancies, suggesting that these agents can induce DNA damage that may be persistent. We have investigated the effect of short exposures (Ͼ3 days) to low etoposide concentrations (LC-etoposide, 0.01-0.04 M) on the ability of leukaemic cells to initiate apoptosis. Results showed that although LC-etoposide had no effect on cell growth characteristics, the pre-culture of cells with LC-etoposide conferred resistance to subsequent exposure to cytotoxic concentrations of etoposide (0.3 M etoposide in HL60 on day 3: %V: 95.2 ± 1.6% vs 60.3 ± 12.1% in control cells with no preculture, and %A: 5.1 ± 0.2 vs 19.0 ± 0.7%; P Ͻ 0.001). This effect was still observed 4 weeks after the initial drug exposure. Associated with these observations was a three-fold increase in genetic instability and a reduction in induced bax protein levels. The anti-cytotoxic effect was also shown to be specific to topoisomerase II (topo II) inhibitors, as the pre-culture of cells with a low doxorubicin concentration also induced resistance, while low cisplatin concentrations did not. The persistence of these alterations in cellular processes following an initial exposure to topo II inhibitors suggests a DNA-based mechanism, and highlights the existence of drug/target interactions even at very low drug concentrations.

show abstract

Lack of correlation between cisplatin-induced apoptosis,p53 status and expression of Bcl-2 family proteins in testicular germ cell tumour cell lines

Cited by 92 publications

References 18 publications

Cisplatin-induced apoptosis in human malignant testicular germ cell lines depends on MEK/ERK activation

Cisplatin-induced apoptosis in human malignant testicular germ cell lines depends on MEK/ERK activation

Low p21Waf1/Cip1 protein level sensitizes testicular germ cell tumor cells to Fas-mediated apoptosis

Exposure to low concentrations of etoposide reduces the apoptotic capability of leukaemic cell lines

Contact Info

Product

Resources

About