Elevation of XPA protein level in testis tumor cells without increasing resistance to cisplatin or UV radiation.
Most testicular germ cell tumors are curable using cisplatin-based chemotherapy, and cell lines from these tumors are unusually sensitive to cisplatin and other DNA-damaging agents. It has been suggested that this might be caused by a lower-than normal nucleotide excision repair (NER) activity. Previous studies found that cell lines from testicular germ cell tumors have on average about one-third the level of the NER protein XPA in comparison to cell lines from other tumors. We asked whether over-expression of XPA protein would alleviate the cellular sensitivity and increase the DNA repair capacity of a testis tumor cell line. Increasing XPA levels in 833K cells by 10-fold did not increase resistance to UV irradiation. XPA was localized to the cell nucleus in all cell lines, before and after exposure to UV-radiation. 833K cells were proficient in removing UV radiation-induced photoproducts from the genome and increased XPA did not enhance the rate of removal. Further, over-expressing functional XPA protein did not correlate with increased resistance of 833K testis tumor cells to cisplatin. Thus, although the amount of XPA in this testis tumor cell line is lower than normal, it is sufficient for NER in vivo. The relative sensitivity of testis tumor cells to cisplatin, UV radiation, and other DNA damaging agents is likely related not to NER capacity, but to other factors such as the integrity of the p53 pathway in these cells.
Köberle
Beate
B
Department of Pharmacology, University of Pittsburgh Medical School and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.
Roginskaya
Vera
V
Zima
Karen S
KS
Masters
John R W
JR
Wood
Richard D
RD
D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry; D004260:DNA Repair; D019281:Dimerization; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D011743:Pyrimidines / Q000737:chemistry; D013736:Testicular Neoplasms / Q000235:genetics* / Q000378:metabolism*; D013737:Testis / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014466:Ultraviolet Rays; D051760:Xeroderma Pigmentosum Group A Protein / Q000096:biosynthesis* / Q000235:genetics
D011743:Pyrimidines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051760:Xeroderma Pigmentosum Group A Protein; D004247:DNA; C030986:pyrimidine; D002945:Cisplatin