Reduced levels of XPA, ERCC1 and XPF DNA repair proteins in testis tumor cell lines

Welsh, Carey; Day, Roger; McGurk, Claire J.; Masters, J. R. W.; Wood, Richard D.; Köberle, Beate

doi:10.1002/ijc.20134

Cited by 198 publications

(157 citation statements)

References 56 publications

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“…Ovarian cancer lines that developed resistance after exposure to cisplatin in vitro were found to have increased ERCC1 levels (Ferry et al, 2000). Most testicular cancer patients are cured by cisplatin (Bosl and Motzer, 1997) and most testicular cancer cell lines have low levels of ERCC1 and XPF (Koberle et al, 1997(Koberle et al, , 1999Welsh et al, 2004). Our data suggest that ERCC1 and XPF induction during cisplatin treatment contribute to the resistance of melanoma to chemotherapy.…”

Section: Discussionmentioning

confidence: 64%

Cisplatin regulates the MAPK kinase pathway to induce increased expression of DNA repair gene ERCC1 and increase melanoma chemoresistance

Melton

2011

Oncogene

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The incidence of malignant melanoma is growing rapidly worldwide and there is still no effective therapy for metastatic disease. Melanoma is the second most common cancer among young adults in the UK, where incidence rates have more than quadrupled since the 1970s. Increased expression of a number of DNA repair genes has been reported in melanoma and this likely contributes to its extreme resistance to conventional DNA-damaging chemotherapeutics. One such chemotherapeutic that is effective against a range of other cancers, but not melanoma, is cisplatin. The DNA repair proteins ERCC1 and XPF are needed to remove cisplatin-induced DNA damage and we have investigated the response of these proteins to cisplatin in melanoma. The expression of both genes is induced by cisplatin. Use of a MEK inhibitor showed that ERCC1, but not XPF induction was regulated by the mitogen-activated protein kinase (MAPK) pathway, with reduction in expression of DUSP6, the phosphatase that inactivates the extracellular signal-regulated kinase (ERK), being particularly important. DUSP6 overexpression prevented cisplatin induction of both ERCC1 and XPF, resulting in increased sensitivity to cisplatin. A novel ERCC1 mRNA was found that initiated upstream of the normal transcription initiation site, and was strongly regulated by both cisplatin and the MAPK pathway and its role in cisplatin resistance merits further study. The cisplatin induction of ERCC1 and XPF provides important insights into the resistance of melanoma to DNA-damaging chemotherapeutics, which is one of the major obstacles to melanoma treatment.

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Section: Discussionmentioning

confidence: 64%

Cisplatin regulates the MAPK kinase pathway to induce increased expression of DNA repair gene ERCC1 and increase melanoma chemoresistance

Melton

2011

Oncogene

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“…The expression levels of ERCC1 and XPF were normalized to RPA protein expression. RPA was chosen because it is a nuclear protein involved in several housekeeping aspects of DNA metabolism, and there was relatively little variation in RPA for cell lines from different tumor types (21).…”

Section: Methodsmentioning

confidence: 99%

“…Using in vitro models, it has been shown that testis tumor cell lines are characterized by reduced levels of ERCC1 and XPF compared to cell lines derived from other types of cancer (21). However, to date no data are available on the expression of ERCC1 and XPF in testicular tumors, although as mentioned above for non-seminomas cisplatin belongs to first-line therapy.…”

Section: Introductionmentioning

confidence: 99%

ERCC1 and XPF expression in human testicular germ cell tumors

Köberle

Brenner²,

Albers³

et al. 2009

Oncol Rep

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Abstract. Nucleotide excision repair (NER) is one of the factors influencing the cellular sensitivity to anticancer drugs. In the present study we compared the expression of the NER proteins ERCC1 and XPF in 24 testicular germ cell tumors (TGCT) with the corresponding normal testicular tissue of the same patient. Using immunoblotting, we demonstrated in TGCT a significant increase of ERCC1 expression compared to the normal tissue. There was no significant increase in XPF expression in TCGT. Based on histological characteristics TGCT are subgrouped into seminomas and non-seminomas, the latter being clinically more aggressive. Investigating ERCC1 levels in seminomas we found a slightly increased expression compared to normal tissue, which was, however, not significant. Similarly, no significant difference was observed for XPF levels in seminomas compared to normal testis tissue. In non-seminomas, however, we found a significant increase in the expression of ERCC1 (p<0.017) and XPF (p<0.03) when compared with the corresponding normal tissue. Comparing seminomas with non-seminomas, we observed a significant increase in the expression of ERCC1 (p<0.05) and XPF (p<0.007) in the non-seminomas. Furthermore, a correlation between the expression of ERCC1 and XPF was observed. Our data demonstrate that non-seminomas are characterized by an increased expression of ERCC1 and XPF protein compared to seminomas and the normal testis tissue. The data indicate a possible up-regulation of ERCC1 and XPF during TGCT progression.

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“…We found that cellular protein extracts of a bladder cancer cell line were proficient for NER (Köberle et al, 1999). Furthermore, the core NER proteins are expressed to a similar extent in bladder cancer cell lines compared to normal non-cancerous cells (Köberle et al, 1999, Welsh et al, 2004. The removal of cisplatin induced DNA platination, which we previously observed in bladder cancer cell lines (Köberle et al, 1997), is therefore, at least in part, due to NER proficiency in these cells.…”

Section: Nucleotide Excision Repairmentioning

confidence: 50%