p53 Hypersensitivity Is the Predominant Mechanism of the Unique Responsiveness of Testicular Germ Cell Tumor (TGCT) Cells to Cisplatin

Gutekunst, Matthias; Oren, Moshe; Weilbacher, Andrea; Dengler, Michael A.; Markwardt, C. B.; Thomale, Jürgen; Aulitzky, Walter E.; Kuip, Heiko van der

doi:10.1371/journal.pone.0019198

Cited by 84 publications

(102 citation statements)

References 50 publications

(58 reference statements)

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“…In addition, when caspase-mediated apoptosis was inhibited in the EC cell line NT2D1 by treatment with Benzyloxycarbonyl-Val-AlaAsp(OMe)-fluoromethylketone (zVADfmk), cells were able to repair cisplatin-induced damage. This suggested that under genotoxic conditions, cisplatin-induced p53-pro-apoptotic response precedes DNA-damage repair, and it is thus the primary cause of TGCT sensitivity to the drug (Gutekunst et al, 2011). However, using gH2AX as a marker of DSBs, we found that prevention of the apoptotic response by zVADfmk, did not rescue the ability of NT2D1 cells to repair DNA damage induced by cisplatin (namely interstrand crosslinks [ICLs]) (Cavallo et al, 2012).…”

Section: The Role Of P53 In Tgct Response To Treatmentmentioning

confidence: 90%

“…In vitro studies have confirmed that the relationship between differentiation and cisplatin-resistance. For example, when the pluripotent EC cell lines, NTERA-2D1 (NT2/D1) and Tera-2 are induced towards terminal differentiation by treatment with retinoic acid, these cells lose their hypersensitivity to cisplatin treatment, (Andrews, 1984, Timmer-Bosscha et al, 1998 even after only 48hs of stimulation (Gutekunst et al, 2011). Surgical resection of residual teratomas is of clinical relevance.…”

Section: P-53-mediated Apoptotic Response and Dna-damage Repair In Tgmentioning

confidence: 99%

“…In addition, comparison of the effects of cisplatin on EC cell lines to its effects on somatic tumor cells revealed that ECs exhibit a hypersensitive reaction to DNA-damage induced increases in p53 protein level via a brisk and strong apoptotic response (Gutekunst et al, 2011). EC are also hypersensitive to the increase in p53 protein level induced by nutlin-3 (Gutekunst et al, 2011, Koster et al, 2011. This result has suggested that regardless of how increased p53 protein level is achieved, EC cells respond by activating the p53-dependent pro-apoptotic pathway, causing rapid and massive cell death.…”

Section: The Role Of P53 In Tgct Response To Treatmentmentioning

confidence: 99%

“…Since nutlin-3 is expected to stabilize p53 in a non-genotoxic manner (B in Fig. 1) (Thompson et al, 2004), the hypersensitive response of EC cells to nutlin-3 also indicates that defects in DNA repair may not be required for EC hypersensitivity to cisplatin (Gutekunst et al, 2011). In addition, when caspase-mediated apoptosis was inhibited in the EC cell line NT2D1 by treatment with Benzyloxycarbonyl-Val-AlaAsp(OMe)-fluoromethylketone (zVADfmk), cells were able to repair cisplatin-induced damage.…”

Section: The Role Of P53 In Tgct Response To Treatmentmentioning

confidence: 99%

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Revisiting DNA damage repair, p53-mediated apoptosis and cisplatin sensitivity in germ cell tumors

Cavallo¹,

Feldman²,

Barchi³

2013

Int. J. Dev. Biol.

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Testicular germ cell tumors (TGCTs), ie, seminomas and nonseminomas, account for 1% to 3% of all neoplasms in men. They are the most common cancer in young white males and are unique in their responsiveness to cisplatin-based chemotherapy. For this reason, TGCTs are considered a model for curative disease. However, up to now, the molecular mechanisms behind this exceptional responsiveness to DNA-damaging agents have remained unclear. A hypersensitive apoptotic response, as well as a reduction in the proficiency to repair cisplatin-induced DNA damage might account for this behavior. In this review, building on recent findings of p53-induced apoptosis and DNA-repair mechanisms in TGCTs, we will discuss the molecular bases that drive tumor sensitivity to cisplatin, emphasizing the new therapeutic approaches proposed to eventually constrain tumor recurrence, and target TGCTs which are unresponsive to standard therapies.

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Section: The Role Of P53 In Tgct Response To Treatmentmentioning

confidence: 90%

Section: P-53-mediated Apoptotic Response and Dna-damage Repair In Tgmentioning

confidence: 99%

Section: The Role Of P53 In Tgct Response To Treatmentmentioning

confidence: 99%

Section: The Role Of P53 In Tgct Response To Treatmentmentioning

confidence: 99%

See 2 more Smart Citations

Revisiting DNA damage repair, p53-mediated apoptosis and cisplatin sensitivity in germ cell tumors

Cavallo¹,

Feldman²,

Barchi³

2013

Int. J. Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…The onset and development of TGCT are complex processes involving multiple factors. Numerous proto-oncogenes and anti-oncogenes, including p53 and c-kit; multiple cell apoptosis genes, including Fas/Fas-L; the expression of the telomerase RNA component; and gene polymorphisms are all implicated in the process of TGCT development (24)(25)(26)(27)(28).…”

Section: Discussionmentioning

confidence: 99%

In vitro study on shRNA-mediated reduction of testis developmental related gene 1 expression and its effects on the proliferation, invasion and apoptosis of NTERA-2 cells

et al. 2015

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Abstract. Testis developmental related gene 1 (TDRG1) is a novel human testis-specific gene. TDRG1 is differentially expressed in cancerous tissue compared with normal testicular tissue and demonstrates a unique expression pattern in normal testes; therefore, this gene may be involved in the occurrence and development of testicular germ cell tumors (TGCT). In the present study, the expression level of TDRG1 was downregulated in human TGCT NTERA-2 cells by RNA interference (RNAi) in order to investigate the association between TDRG1 and TGCT. The TDRG1 mRNA and protein expression levels in NTERA-2 cells were significantly inhibited following transfection with specific RNAi plasmids. The ability to proliferate (inhibited by 15.4% at day 3 and 26.1% at day 5; P<0.001) and invade (reduced by 49.1%; P=0.01) in vitro was suppressed in cells in which the expression level of TDRG1 was reduced, and a corresponding increase in the apoptotic potential was observed (the early apoptotic potential and total apoptotic potential were increased by 75%; P=0.019 and 54.8%; P=0.009, respectively). The results of the present study indicated that the biological behavior of NTERA-2 cells is associated with TDRG1 expression levels, and that this gene may be a novel target candidate in the treatment of TGCT.

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MicroRNA‐302a sensitizes testicular embryonal carcinoma cells to cisplatin‐induced cell death

Liu

Lian

Zhang

et al. 2013

Journal Cellular Physiology

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Cisplatin is a commonly used chemotherapeutic agent for the treatment of several human malignancies, such as testicular germ cell tumors (TGCT). The toxic effects persist and those that are present long after chemotherapy affect the overall quality of life of patients. MicroRNAs (miRNAs) play important roles in the responses of cancer cells to chemotherapy and have been shown to modulate cell sensitivity to chemotherapeutic drugs. However, the relationship between miRNA expression and cisplatin sensitivity of TGCT has not been fully explored. In this study, the effects of miR-302a on cisplatin cytotoxicity in TGCT-derived cell line NTERA-2 (NT2) were evaluated. We found that expression levels of miR-302a were increased in cisplatin-treated NT2 cells. Up-regulation of miR-302a significantly increased the sensitivity of NT2 cells to cisplatin by enhancing cisplatin-induced G2/M phase arrest and the subsequent progression to apoptosis. MiR-302a also increased the killing effects of cisplatin by lowering the apoptotic threshold; the same result was also observed in another TGCT-derived cell line, NCCIT. Furthermore, miR-302a-enhanced cisplatin sensitivity was partially mediated through the down-regulation of p21 in NT2 cells. MiR-302a induced apoptosis was further enhanced by silencing of p53 in NT2 cells. p53 levels were inversely associated with the expression of Oct4, Sox2, and Nanog in response to cisplatin. Thus, targeting miR-302a may offer new therapeutic interventions in TGCT.

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p53 Hypersensitivity Is the Predominant Mechanism of the Unique Responsiveness of Testicular Germ Cell Tumor (TGCT) Cells to Cisplatin

Cited by 84 publications

References 50 publications

Revisiting DNA damage repair, p53-mediated apoptosis and cisplatin sensitivity in germ cell tumors

Revisiting DNA damage repair, p53-mediated apoptosis and cisplatin sensitivity in germ cell tumors

In vitro study on shRNA-mediated reduction of testis developmental related gene 1 expression and its effects on the proliferation, invasion and apoptosis of NTERA-2 cells

MicroRNA‐302a sensitizes testicular embryonal carcinoma cells to cisplatin‐induced cell death

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