p53 Hypersensitivity Is the Predominant Mechanism of the Unique Responsiveness of Testicular Germ Cell Tumor (TGCT) Cells to Cisplatin

Autor: Christiane Markwardt, Heiko van der Kuip, Andrea Weilbacher, Jürgen Thomale, Michael A. Dengler, Moshe Oren, Matthias Gutekunst, Walter E. Aulitzky
Rok vydání: 2011
Předmět:
Male
Urology
Cellular differentiation
Medizin
Cancer Treatment
Testicular Germ Cell Tumor
lcsh:Medicine
Antineoplastic Agents
Embryonal carcinoma
Testicular Neoplasms
Cell Line
Tumor
Molecular Cell Biology
Germ Cell Cancer
Testicular Cancer
medicine
Humans
Signaling in Cellular Processes
lcsh:Science
Biology
DNA Primers
Apoptotic Signaling
Cellular Stress Responses
Cisplatin
Multidisciplinary
Base Sequence
Cell Death
biology
Reverse Transcriptase Polymerase Chain Reaction
Bortezomib
lcsh:R
Cancers and Neoplasms
Neoplasms
Germ Cell and Embryonal
Chemotherapy and Drug Treatment
medicine.disease
Molecular biology
Oncology
Cell culture
biology.protein
Cancer research
Proteasome inhibitor
Medicine
Mdm2
lcsh:Q
Tumor Suppressor Protein p53
Gynecological Tumors
Research Article
Signal Transduction
medicine.drug
Zdroj: PLoS ONE, Vol 6, Iss 4, p e19198 (2011)
PLoS ONE
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0019198
Popis: 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. © 2011 Gutekunst et al.
Databáze: OpenAIRE
Externí odkaz: