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

Grande, Lara; Bretones, Gabriel; Rosa‐Garrido, Manuel; Garrido-Martin, Eva M.; Hernández, Teresa; Fraile, Susana; Botella, Luisa María; Álava, Enrique de; Vidal, August; Muro, Xavier García del; Villanueva, Alberto; Delgado, M. Dolores; Fernández-Luna, José L.

doi:10.1074/jbc.m112.376319

Cited by 45 publications

(46 citation statements)

References 50 publications

(44 reference statements)

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“…S2). The prominent role of Noxa for TGCT hypersensitivity is further supported by the finding that Noxa protein was found to be correlated with good clinical prognosis in patients with embryonal carcinoma (34).…”

Section: Discussionsupporting

confidence: 56%

Cisplatin Hypersensitivity of Testicular Germ Cell Tumors Is Determined by High Constitutive Noxa Levels Mediated by Oct-4

et al. 2013

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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. Cancer Res; 73(5);

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Section: Discussionsupporting

confidence: 56%

Cisplatin Hypersensitivity of Testicular Germ Cell Tumors Is Determined by High Constitutive Noxa Levels Mediated by Oct-4

et al. 2013

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“…Nevertheless, other mechanisms could be involved, such as miRNA regulation or transcription factor activity. All of these mechanisms are regulated by CDDP in various tumor cell types (15,28).…”

Section: Discussionmentioning

confidence: 99%

“…Labeling frequency was scored as the percentage of positive tumoral cells. The multiplicative index of intensity and labeling frequency was used in our analysis, as previously described (15).…”

Section: Immunohistochemistry In Human Samples and Scoringmentioning

confidence: 99%

The PDGFRβ–AKT Pathway Contributes to CDDP-Acquired Resistance in Testicular Germ Cell Tumors

Juliachs

Muñoz

Moutinho

et al. 2014

Clinical Cancer Research

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Purpose: We examined whether PI3K-AKT or extracellular signal-regulated kinase (ERK) signaling pathways could play a role in the development of cisplatin (CDDP) resistance in testicular germ cell tumor (TGT) cells.Experimental Design: We compared AKT and ERK activation levels in CDDP-sensitive testicular tumor cells and in their corresponding CDDP-resistant-derived cells. We also analyzed these pathways in orthotopic testicular tumors and human patient samples.Results: Our results indicated that there was overactivation of AKT in CDDP-resistant cells compared with sensitive cells, but no effect on activated ERK levels. We observed an increase in mRNA and protein levels for platelet-derived growth factor (PDGF) receptor b and PDGF-B ligand. These were responsible for AKT overactivation in CDDP-resistant cells. When PDGFRb levels were decreased by short hairpin RNA (shRNA) treatment or its activation was blocked by pazopanib, CDDP-resistant cells behaved like sensitive cells. Moreover, CDDP-resistant cells were more sensitive to incubation with PDGFRb inhibitors such as pazopanib or sunitinib than sensitive cells, a finding consistent with these cells being dependent on this signaling pathway. We also found overexpression of PDGFRb and pAKT in CDDP-resistant choriocarcinoma orthotopic tumor versus their CDDP-sensitive counterparts. Finally, we found high PDGFRb levels in human testicular tumors, and overexpression in CDDP-resistant testicular choriocarcinomas compared with the CDDP-sensitive and nontreated tumors.Conclusions: The PDGFRb-AKT pathway plays a critical role in the development of CDDP resistance in testicular tumoral cells. Clin Cancer Res; 20(3); 658-67. Ó2013 AACR.

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“…Interestingly, Noxa was found to be significantly higher expressed in tumours of TC patients with blood markers predicting a good clinical prognosis (Ref. 112).…”

Section: Cisplatin-induced Apoptosis In Testicular Cancermentioning

confidence: 98%

Unravelling mechanisms of cisplatin sensitivity and resistance in testicular cancer

Koster

Vugt

Timmer‐Bosscha

et al. 2013

Expert Rev. Mol. Med.

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Testicular cancer is the most frequent solid malignant tumour type in men 20-40 years of age. At the time of diagnosis up to 50% of the patients suffer from metastatic disease. In contrast to most other metastatic solid tumours, the majority of metastatic testicular cancer patients can be cured with highly effective cisplatin-based chemotherapy. This review aims to summarise the current knowledge on response to chemotherapy and the biological basis of cisplatin-induced apoptosis in testicular cancer. The frequent presence of wild-type TP53 and the low levels of p53 in complex with the p53 negative feed-back regulator MDM2 contribute to cisplatin sensitivity. Moreover, the high levels of the pluripotency regulator Oct4 and as a consequence of Oct4 expression high levels of miR-17/106b seed family and pro-apoptotic Noxa and the low levels of cytoplasmic p21 (WAF1/Cip1) appear to be causative for the exquisite sensitivity to cisplatin-based therapy of testicular cancer. However, resistance of testicular cancer to cisplatin-based therapy does occur and can be mediated through aberrant levels of the above mentioned key players. Drugs targeting these key players showed, at least pre-clinically, a sensitising effect to cisplatin treatment. Further clinical development of such treatment strategies will lead to new treatment options for platinum-resistant testicular cancers.

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

Cited by 45 publications

References 50 publications

Cisplatin Hypersensitivity of Testicular Germ Cell Tumors Is Determined by High Constitutive Noxa Levels Mediated by Oct-4

Cisplatin Hypersensitivity of Testicular Germ Cell Tumors Is Determined by High Constitutive Noxa Levels Mediated by Oct-4

The PDGFRβ–AKT Pathway Contributes to CDDP-Acquired Resistance in Testicular Germ Cell Tumors

Unravelling mechanisms of cisplatin sensitivity and resistance in testicular cancer

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