title: p53 hypersensitivity is the predominant mechanism of the unique responsiveness of testicular germ cell tumor (TGCT) cells to cisplatin.
abstract: Consistent with the excellent clinical results in testicular germ cell tumors (TGCT), most cell lines derived from this cancer show an exquisite sensitivity to Cisplatin. It is well accepted that the high susceptibility of TGCT cells to apoptosis plays a central role in this hypersensitive phenotype. The role of the tumor suppressor p53 in this response, however, remains controversial. Here we show that siRNA-mediated silencing of p53 is sufficient to completely abrogate hypersensitivity not only to Cisplatin but also to non-genotoxic inducers of p53 such as the Mdm2 antagonist Nutlin-3 and the proteasome inhibitor Bortezomib. The close relationship between p53 protein levels and induction of apoptosis is lost upon short-term differentiation, indicating that this predominant pro-apoptotic function of p53 is unique in pluripotent embryonal carcinoma (EC) cells. RNA interference experiments as well as microarray analysis demonstrated a central role of the pro-apoptotic p53 target gene NOXA in the p53-dependent apoptotic response of these cells. In conclusion, our data indicate that the hypersensitivity of TGCT cells is a result of their unique sensitivity to p53 activation. Furthermore, in the very specific cellular context of germ cell-derived pluripotent EC cells, p53 function appears to be limited to induction of apoptosis.
authors.affiliation: Dr Margarete-Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gutekunst
authors.forename: Moshe
authors.initials: M
authors.lastname: Oren
authors.forename: Andrea
authors.initials: A
authors.lastname: Weilbacher
authors.forename: Michael A
authors.initials: MA
authors.lastname: Dengler
authors.forename: Christiane
authors.initials: C
authors.lastname: Markwardt
authors.forename: Jürgen
authors.initials: J
authors.lastname: Thomale
authors.forename: Walter E
authors.initials: WE
authors.lastname: Aulitzky
authors.forename: Heiko
authors.initials: H
authors.lastname: van der Kuip
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D017931:DNA Primers; D006801:Humans; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013736:Testicular Neoplasms / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; D017931:DNA Primers; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin