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Gutekunst, M; Mueller, T; Weilbacher, A; Dengler, MA; Bedke, J; Kruck, S; Oren, M; Aulitzky, WE; van der Kuip, H.
Cisplatin hypersensitivity of testicular germ cell tumors is determined by high constitutive Noxa levels mediated by Oct-4.
Cancer Res. 2013; 73(5):1460-1469 Doi: 10.1158/0008-5472.CAN-12-2876
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Co-Autor*innen der Med Uni Graz
Dengler Michael

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Testicular germ cell tumors (TGCT) are considered a paradigm of chemosensitive tumors. Embryonal carcinoma cells represent the pluripotent entity of TGCTs and are characterized by expression of Oct-4, a key regulator of pluripotency and a determinant of their inherent hypersensitivity to cisplatin. However, the mechanisms underlying this Oct-4-mediated sensitivity are poorly understood. We previously showed that p53 is a major player in cisplatin hypersensitivity and therefore investigated whether Oct-4 may directly affect p53 activity. Despite a significant decrease in sensitivity, depletion of Oct-4 neither did alter cisplatin-induced transactivation of p53 target genes nor its subcellular localization. These data indicate that, rather than directly modulating p53 activity, Oct-4 provides a cellular context that augments the proapoptotic activity of p53. As mitochondrial priming by the Bcl-2 family is a known determinant of chemosensitivity, we compared the constitutive levels of these proteins in Oct-4-positive and -depleted cells. We identified Noxa as the only Bcl-2 family protein to be highly correlated with Oct-4 status and cisplatin sensitivity. Compared with differentiated cells, constitutive Noxa levels were significantly higher in Oct-4-positive cell lines and cancer patient samples. Furthermore, RNA interference-mediated knockdown of Oct-4 resulted in reduced Noxa transcript, in an almost complete loss of constitutive Noxa protein and decreased cisplatin hypersensitivity to a similar extent as did Noxa depletion. In conclusion, our study indicates that Noxa is a central determinant of hypersensitivity to cisplatin. Oct-4-dependent high constitutive levels of this BH3-only protein prime embryonal carcinoma cells to undergo rapid and massive apoptosis in response to p53 activation. ©2012 AACR
Find related publications in this database (using NLM MeSH Indexing)
Apoptosis - drug effects
Cell Line, Tumor -
Cisplatin - pharmacology
Gene Knockdown Techniques -
Humans -
Male -
Neoplasms, Germ Cell and Embryonal - drug therapy
Neoplasms, Germ Cell and Embryonal - genetics
Octamer Transcription Factor-3 - metabolism
Proto-Oncogene Proteins c-bcl-2 - genetics
Proto-Oncogene Proteins c-bcl-2 - metabolism
Testicular Neoplasms - drug therapy
Testicular Neoplasms - genetics
Tumor Suppressor Protein p53 - metabolism

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