Abstract
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.
Highlights
Testicular germ cell tumors (TGCT) are the most frequent carcinomas in young male adults with a still increasing incidence worldwide
It has previously been shown that Oct-4 protein levels are highly correlated with cisplatin hypersensitivity in TGCT cells [6]
Oct-4 depletion reduced Nutlin-3–induced apoptosis to a degree comparable to that observed in cells treated with cisplatin. These results suggest that efficient induction of apoptosis by p53 requires the pluripotent, Oct-4–positive context of embryonal carcinoma cells
Summary
Testicular germ cell tumors (TGCT) are the most frequent carcinomas in young male adults with a still increasing incidence worldwide. Cisplatin-based chemotherapy cures the majority of patients even in advanced stages due to the extraordinary sensitivity of TGCTs to cisplatin. TGCTs are considered as the paradigm of a chemosensitive tumor [1]. Several mechanisms have been considered to underlie this hypersensitivity, including the high apoptotic propensity of TGCT cells [2, 3]. Authors' Affiliations: 1Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen; 22nd Department of Internal Medicine, Oncology and Hematology, Robert Bosch Hospital, Stuttgart; 3Department of Internal Medicine IV, Oncology and Hematology, MartinLuther-University of Halle-Wittenberg, Halle; 4Department of Urology, Eberhard Karls University of Tuebingen, Tuebingen, Germany; and 5Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
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