Transcription Factors Sp1 and p73 Control the Expression of the Proapoptotic Protein NOXA in the Response of Testicular Embryonal Carcinoma Cells to Cisplatin

Testicular germ cell tumors (TGCTs) are highly responsive to and curable by cisplatin-based chemotherapy even in advanced stages. We have studied the molecular mechanisms involved in the induction of apoptosis in response to cisplatin, and found that proapoptotic Noxa is transcriptionally up-regulat...

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Published in:The Journal of biological chemistry 2012-08, Vol.287 (32), p.26495-26505
Main Authors: Grande, Lara, Bretones, Gabriel, Rosa-Garrido, Manuel, Garrido-Martin, Eva M., Hernandez, Teresa, Fraile, Susana, Botella, Luisa, de Alava, Enrique, Vidal, August, Garcia del Muro, Xavier, Villanueva, Alberto, Delgado, M. Dolores, Fernandez-Luna, Jose L.
Format: Article
Language:English
Subjects:
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Apoptosis
Apoptosis - physiology
Base Sequence
Bcl-2 Family Proteins
Cancer Biology
Carcinoma, Embryonal - drug therapy
Carcinoma, Embryonal - genetics
Carcinoma, Embryonal - pathology
Cell Line, Tumor
Chemoresistance
Cisplatin - pharmacology
Cisplatin - therapeutic use
Cohort Studies
DNA Primers
DNA-Binding Proteins - physiology
Embryonal Carcinoma
Gene Expression Regulation, Neoplastic - drug effects
Gene Expression Regulation, Neoplastic - physiology
Gene Regulation
Humans
Male
Noxa
Nuclear Proteins - physiology
Prognosis
Promoter Regions, Genetic
Proto-Oncogene Proteins c-bcl-2 - genetics
Real-Time Polymerase Chain Reaction
Sp1 Transcription Factor - physiology
Sp1-like Factors
Testicular Neoplasms - drug therapy
Testicular Neoplasms - genetics
Testicular Neoplasms - pathology
Transcription Regulation
Tumor Protein p73
Tumor Suppressor Proteins - physiology
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Summary:Testicular germ cell tumors (TGCTs) are highly responsive to and curable by cisplatin-based chemotherapy even in advanced stages. We have studied the molecular mechanisms involved in the induction of apoptosis in response to cisplatin, and found that proapoptotic Noxa is transcriptionally up-regulated following cisplatin exposure, even in the absence of p53, in NTERA2 cisplatin-sensitive cells but not in 1411HP-resistant cells. Blockade of Noxa reduced the apoptotic response of embryonal carcinoma (EC) NTERA2 cells to cisplatin. A detailed analysis of the Noxa promoter revealed that p73 and Sp1-like factors, Sp1 and KLF6, played key roles in the transcriptional control of this gene. Overexpression of TAp73 induced Noxa whereas the dominant negative isoform ΔNp73, reduced the levels of Noxa after cisplatin exposure in NTERA2 and 2102EP. Interestingly, down-regulation of Sp1 increased Noxa expression in response to cisplatin. However, blockade of KLF6 decreased cisplatin-induced up-regulation of Noxa in EC cell lines. In addition, tissue microarray analyses of TGCTs revealed that expression of Noxa correlates with good clinical prognosis in patients with embryonal carcinoma. Thus, our data show the transcriptional network that regulates Noxa in EC cells, which is key for their apoptotic response to cisplatin-based chemotherapy, and propose Noxa as a predictive factor of therapeutic response. Background: There is little understanding of the mechanisms that explain why testicular germ cell tumors respond so well to chemotherapy. Results: Noxa is transcriptionally activated by KLF6 and TAp73 and repressed by Sp1 and ΔNp73, and its protein levels correlate with clinical prognosis. Conclusion: p73 isoforms and Sp1-like factors form a cisplatin-induced transcriptional network that regulate proapoptotic Noxa. Significance: This might help understand the transcriptional pathways of chemosensitivity.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M112.376319