Cellular basis for differential sensitivity to cisplatin in human germ cell tumour and colon carcinoma cell lines

Sark, Mwj; Timmer‐Bosscha, Hetty; Meijer, Coby; Uges, Donald; Sluiter, Willem; Peters, Whm; Mulder, Nanno; Vries, de Elisabeth G. E.

doi:10.1038/bjc.1995.135

Cited by 52 publications

(44 citation statements)

References 24 publications

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“…However, analysis of potentially relevant parameters, including cellular detoxification mechanisms (e.g. the glutathione and the metallothionein systems), Pt accumulation, DNA platination and repair, and topoisomerase activity have not been able, so far, to elucidate the nature of this exceptional sensitivity (Sark et al, 1995). In the present study, we investigated the susceptibility of a panel of four TGCT cell lines to cisplatin-induced apoptosis and evaluated the role of p53, Bcl-2 and Bax.…”

Section: Isolation and Sequencing Of P53 Cdnasmentioning

confidence: 99%

Expression of p53, Bcl-2 and Bax in cisplatin-induced apoptosis in testicular germ cell tumour cell lines

Burger

Nooter²,

Boersma³

et al. 1998

Br J Cancer

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Summary We examined the sensitivity for cisplatin-induced apoptosis in a panel of four testicular germ cell tumour (TGCT) cell lines and monitored the cellular expression of the apoptosis-related proteins p53, Bcl-2 and Bax. Three of four TGCT cell lines (NT2, NCCIT and S2) were hypersensitive for cisplatin-induced apoptosis, while the TGCT cell line 2102 EP appeared to be resistant for cisplatin-induced apoptosis, even at relatively high drug concentrations (12.5 IIM). For all four cell lines, the induction of apoptosis by cisplatin correlated with drug sensitivity in the MTT assay. The differences in chemosensitivity and induction of apoptosis could not be attributed to differences in cellular platinum accumulation, DNA platination or platinum-DNA adduct removal. We next analysed the relationship between p53 status and cisplatin-induced up-regulation of p53, and the susceptibility to cisplatin-induced apoptosis. Wild-type p53 containing NT2 and 2102 EP cells showed p53 up-regulation upon drug treatment, and NCCIT (mutant p53) and S2 (no p53 protein) cells did not. Consistently, the increase in wild-type p53 protein in NT2 and 2102 EP cells led to an increase in mRNA level of the p53 downstream gene p21/WA/F/C/P, whereas mutant p53-containing NCCIT cells and p53-non-expressing S2 cells could not transactivate this p53-responsive gene. As NT2, NCCIT and S2 were readily triggered into apoptosis, while 2102 EP cells failed to undergo cisplatin-induced apoptosis, our data suggest that the presence of wildtype and/or transactivation-competent p53 might not be an absolute prerequisite for efficient induction of apoptosis in TGCT cell lines. Also endogenous levels of Bcl-2 and Bax expression did not correlate with cisplatin-induced apoptosis. In addition, the endogenous Bcl-2 and Bax expression was not affected by cisplatin treatment. The present study suggests that, at least in our panel of TGCT cell lines, hypersensitivity for cisplatin-induced apoptosis might not be necessarily correlated with the presence of wild-type p53 and is probably not associated with Bcl-2 and Bax expression.

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Section: Isolation and Sequencing Of P53 Cdnasmentioning

confidence: 99%

Expression of p53, Bcl-2 and Bax in cisplatin-induced apoptosis in testicular germ cell tumour cell lines

Burger

Nooter²,

Boersma³

et al. 1998

Br J Cancer

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“…The TGCT cell lines Tera and Scha were described previously (Sark et al, 1995). Both Tera and Scha revealed no Fas mutations (Spierings et al, 2003a).…”

Section: Cell Linesmentioning

confidence: 99%

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

et al. 2004

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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.

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“…In any case, if the damage is unrepairable, then cell death (apoptosis) provides a fallback mechanism by which genomic integrity is maintained. In past years, the clinical and in vitro evidence of collateral sensitivity to multiple agents suggested that it is the signaling of DNA damage (the downstream events) that differ in cancer cells, which resulted in chemosensitivity (Bedford et al, 1998;Hill et al, 1994;Koberle et al, 1997;Sark et al, 1995). One of the highly studied DNA damage-induced downstream signaling molecules is p53, which by regulating p21 gene expression causes cell cycle arrest and apoptosis in target cells (Jaiswal and Narayan, 2002; reviewed by Boulaire et al, 2000;Prosperi, 1997;Taylor and Stark, 2001).…”

Section: Introductionmentioning

confidence: 99%

Long-patch base excision repair of apurinic/apyrimidinic site DNA is decreased in mouse embryonic fibroblast cell lines treated with plumbagin: involvement of cyclin-dependent kinase inhibitor p21Waf-1/Cip-1

2002

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Molecular interactions among cell cycle and DNA repair proteins have been described, but the impact of many of these interactions on cell cycle control and DNA repair remains unclear. The cyclin-dependent kinase inhibitor, p21, is known to be involved in DNA damage-induced cell cycle arrest and blocking DNA replication and repair. Participation of p21 has been implicated in nucleotide excision repair. However, the role of p21 in the base excision repair (BER) pathway has not been thoroughly studied. In the present investigation, we treated isogenic mouse embryonic fibroblast (MEF) cell lines containing wild-type (MEF-polb) or DNA polymerase b (polb) gene-knockout (MEFpolbKO) with oxidative DNA-damaging agent, plumbagin, and examined its effect on p21 levels and BER activity. Plumbagin treatment caused a S-G 2 /M phase arrest and cell death of both MEF cell lines, induced p21 levels, and decreased p21-mediated long-patch (LP) BER by blocking DNA ligase activity in the polb-dependent pathway and by blocking both FEN1 and DNA ligase activity in polbindependent pathway. These findings suggest that plumbagin induced p21 levels play a regulatory role in cell cycle arrest, apoptosis, and polb-dependent and -independent LP-BER pathways in MEF cells.

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Cellular basis for differential sensitivity to cisplatin in human germ cell tumour and colon carcinoma cell lines

Cited by 52 publications

References 24 publications

Expression of p53, Bcl-2 and Bax in cisplatin-induced apoptosis in testicular germ cell tumour cell lines

Expression of p53, Bcl-2 and Bax in cisplatin-induced apoptosis in testicular germ cell tumour cell lines

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

Long-patch base excision repair of apurinic/apyrimidinic site DNA is decreased in mouse embryonic fibroblast cell lines treated with plumbagin: involvement of cyclin-dependent kinase inhibitor p21Waf-1/Cip-1

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