scholarly journals Testicular Germ Cell Tumors Acquire Cisplatin Resistance by Rebalancing the Usage of DNA Repair Pathways

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 787
Author(s):  
Cinzia Caggiano ◽  
Francesca Cavallo ◽  
Teresa Giannattasio ◽  
Gioia Cappelletti ◽  
Pellegrino Rossi ◽  
...  
Keyword(s):  
Germ Cell ◽  
Cell Lines ◽  
Cisplatin Resistance ◽  
Parp Inhibitor ◽  
Acquired Resistance ◽  
Germ Cell Tumors ◽  
Resistant Cell ◽  
High Rate ◽  
Dna Double Strand Breaks ◽  
Testicular Germ Cell

Despite germ cell tumors (GCTs) responding to cisplatin-based chemotherapy at a high rate, a subset of patients does not respond to treatment and have significantly worse prognosis. The biological mechanisms underlying the resistance remain unknown. In this study, by using two TGCT cell lines that have acquired cisplatin resistance after chronic exposure to the drug, we identified some key proteins and mechanisms of acquired resistance. We show that cisplatin-resistant cell lines had a non-homologous end-joining (NHEJ)-less phenotype. This correlated with a reduced basal expression of TP53-binding protein 1 (53BP1) and DNA-dependent protein kinase (DNA-PKcs) proteins and reduced formation of 53BP1 foci after cisplatin treatment. Consistent with these observations, modulation of 53BP1 protein expression altered the cell line’s resistance to cisplatin, and inhibition of DNA-PKcs activity antagonized cisplatin cytotoxicity. Dampening of NHEJ was accompanied by a functional increase in the repair of DNA double-strand breaks (DSBs) by the homologous recombination repair pathway. As a result, cisplatin-resistant cells were more resistant to PARP inhibitor (PARPi) monotherapy. Moreover, when PARPi was given in combination with cisplatin, it exerted an additive/synergistic effect, and reduced the cisplatin dose for cytotoxicity. These results suggest that treatment of cisplatin-refractory patients may benefit from low-dose cisplatin therapy combined with PARPi.

scholarly journals Efficacy of HDAC Inhibitors Belinostat and Panobinostat against Cisplatin-Sensitive and Cisplatin-Resistant Testicular Germ Cell Tumors

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2903 ◽  
Author(s):  
João Lobo ◽  
Catarina Guimarães-Teixeira ◽  
Daniela Barros-Silva ◽  
Vera Miranda-Gonçalves ◽  
Vânia Camilo ◽  
...  
Keyword(s):  
Germ Cell ◽  
Cell Lines ◽  
Cisplatin Resistance ◽  
Treatment Options ◽  
Hdac Inhibitors ◽  
Germ Cell Tumors ◽  
Testicular Germ Cell Tumor ◽  
Testicular Germ Cell ◽  
Cycle Arrest ◽  
First Time

Novel treatment options are needed for testicular germ cell tumor (TGCT) patients, particularly important for those showing or developing cisplatin resistance, the major cause of cancer-related deaths. As TGCTs pathobiology is highly related to epigenetic (de)regulation, epidrugs are potentially effective therapies. Hence, we sought to explore, for the first time, the effect of the two most recently FDA-approved HDAC inhibitors (HDACis), belinostat and panobinostat, in (T)GCT cell lines including those resistant to cisplatin. In silico results were validated in 261 patient samples and differential expression of HDACs was also observed across cell lines. Belinostat and panobinostat reduced cell viability in both cisplatin-sensitive cells (NCCIT-P, 2102Ep-P, and NT2-P) and, importantly, also in matched cisplatin-resistant subclones (NCCIT-R, 2102Ep-R, and NT2-R), with IC50s in the low nanomolar range for all cell lines. Treatment of NCCIT-R with both drugs increased acetylation, induced cell cycle arrest, reduced proliferation, decreased Ki67 index, and increased p21, while increasing cell death by apoptosis, with upregulation of cleaved caspase 3. These findings support the effectiveness of HDACis for treating TGCT patients in general, including those developing cisplatin resistance. Future studies should explore them as single or combination agents.

Molecular Mechanisms of Resistance in Testicular Germ Cell Tumors - clinical Implications

2018 ◽  
Vol 18 (10) ◽  
pp. 967-978 ◽  
Author(s):  
Katarina Kalavska ◽  
Vincenza Conteduca ◽  
Ugo De Giorgi ◽  
Michal Mego
Keyword(s):  
Germ Cell ◽  
Molecular Mechanisms ◽  
Cisplatin Resistance ◽  
Apoptotic Cell ◽  
Germ Cell Tumors ◽  
Treatment Resistance ◽  
Experimental Models ◽  
Testicular Germ Cell Tumors ◽  
Testicular Germ Cell ◽  
Repair Capacity

Testicular germ cell tumors (TGCTs) represent the most common malignancy in men aged 15-35. Due to these tumors’ biological and clinical characteristics, they can serve as an appropriate system for studying molecular mechanisms associated with cisplatin-based treatment resistance. This review describes treatment resistance from clinical and molecular viewpoints. Cisplatin resistance is determined by various biological mechanisms, including the modulation of the DNA repair capacity of cancer cells, alterations to apoptotic cell death pathways, deregulation of gene expression pathways, epigenetic alterations and insufficient DNA binding. Moreover, this review describes TGCTs as a model system that enables the study of the cellular features of cancer stem cells in metastatic process and describes experimental models that can be used to study treatment resistance in TGCTs. All of the abovementioned aspects may help to elucidate the molecular mechanisms underlying cisplatin resistance and may help to identify promising new therapeutic targets.

scholarly journals Epigenetic Remodeling through Downregulation of Polycomb Repressive Complex 2 Mediates Chemotherapy Resistance in Testicular Germ Cell Tumors

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 796 ◽  
Author(s):  
Ratnakar Singh ◽  
Zeeshan Fazal ◽  
Andrea K. Corbet ◽  
Emmanuel Bikorimana ◽  
Jennifer C. Rodriguez ◽  
...  
Keyword(s):  
Germ Cell ◽  
Cisplatin Resistance ◽  
Germ Cell Tumors ◽  
Parental Origin ◽  
Testicular Germ Cell Tumors ◽  
Polycomb Repressive Complex ◽  
Testicular Germ Cell ◽  
Polycomb Repressive Complex 2 ◽  
H3k27 Methylation ◽  
Resistant Cells

A greater understanding of the hypersensitivity and curability of testicular germ cell tumors (TGCTs) has the potential to inform strategies to sensitize other solid tumors to conventional chemotherapies. The mechanisms of cisplatin hypersensitivity and resistance in embryonal carcinoma (EC), the stem cells of TGCTs, remain largely undefined. To study the mechanisms of cisplatin resistance we generated a large panel of independently derived, acquired resistant clones from three distinct parental EC models employing a protocol designed to match standard of care regimens of TGCT patients. Transcriptomics revealed highly significant expression changes shared between resistant cells regardless of their parental origin. This was dominated by a highly significant enrichment of genes normally repressed by H3K27 methylation and the polycomb repressive complex 2 (PRC2) which correlated with a substantial decrease in global H3K27me3, H2AK119 ubiquitination, and expression of BMI1. Importantly, repression of H3K27 methylation with the EZH2 inhibitor GSK-126 conferred cisplatin resistance to parental cells while induction of H3K27 methylation with the histone lysine demethylase inhibitor GSK-J4 resulted in increased cisplatin sensitivity to resistant cells. A gene signature based on H3K27me gene enrichment was associated with an increased rate of recurrent/progressive disease in testicular cancer patients. Our data indicates that repression of H3K27 methylation is a mechanism of cisplatin acquired resistance in TGCTs and that restoration of PRC2 complex function is a viable approach to overcome treatment failure.

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

2013 ◽  
Vol 20 (3) ◽  
pp. 658-667 ◽  
Author(s):  
M. Juliachs ◽  
C. Muñoz ◽  
C.A. Moutinho ◽  
A. Vidal ◽  
E. Condom ◽  
...  
Keyword(s):  
Germ Cell ◽  
Acquired Resistance ◽  
Germ Cell Tumors ◽  
Akt Pathway ◽  
Testicular Germ Cell Tumors ◽  
Testicular Germ Cell

Orthoxenografts of Testicular Germ Cell Tumors Demonstrate Genomic Changes Associated with Cisplatin Resistance and Identify PDMP as a Resensitizing Agent

2018 ◽  
Vol 24 (15) ◽  
pp. 3755-3766 ◽  
Author(s):  
Josep M. Piulats ◽  
August Vidal ◽  
Francisco J. García-Rodríguez ◽  
Clara Muñoz ◽  
Marga Nadal ◽  
...  
Keyword(s):  
Germ Cell ◽  
Cisplatin Resistance ◽  
Germ Cell Tumors ◽  
Testicular Germ Cell Tumors ◽  
Testicular Germ Cell ◽  
Genomic Changes

scholarly journals The component of the m6A writer complex VIRMA is implicated in aggressive tumor phenotype, DNA damage response and cisplatin resistance in germ cell tumors

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Vera Miranda-Gonçalves ◽  
João Lobo ◽  
Catarina Guimarães-Teixeira ◽  
Daniela Barros-Silva ◽  
Rita Guimarães ◽  
...  
Keyword(s):  
Dna Damage ◽  
Germ Cell ◽  
Differential Expression ◽  
Cell Lines ◽  
Cisplatin Resistance ◽  
Germ Cell Tumors ◽  
Migration And Invasion ◽  
In Vivo Models

Abstract Background Germ cell tumors (GCTs) are developmental cancers, tightly linked to embryogenesis and germ cell development. The recent and expanding field of RNA modifications is being increasingly implicated in such molecular events, as well as in tumor progression and resistance to therapy, but still rarely explored in GCTs. In this work, and as a follow-up of our recent study on this topic in TGCT tissue samples, we aim to investigate the role of N6-methyladenosine (m6A), the most abundant of such modifications in mRNA, in in vitro and in vivo models representative of such tumors. Methods Four cell lines representative of GCTs (three testicular and one mediastinal), including an isogenic cisplatin resistant subline, were used. CRISPR/Cas9-mediated knockdown of VIRMA was established and the chorioallantoic membrane assay was used to study its phenotypic effect in vivo. Results We demonstrated the differential expression of the various m6A writers, readers and erasers in GCT cell lines representative of the major classes of these tumors, seminomas and non-seminomas, and we evidenced changes occurring upon differentiation with all-trans retinoic acid treatment. We showed differential expression also among cells sensitive and resistant to cisplatin treatment, implicating these players in acquisition of cisplatin resistant phenotype. Knockdown of VIRMA led to disruption of the remaining methyltransferase complex and decrease in m6A abundance, as well as overall reduced tumor aggressiveness (with decreased cell viability, tumor cell proliferation, migration, and invasion) and increased sensitivity to cisplatin treatment, both in vitro and confirmed in vivo. Enhanced response to cisplatin after VIRMA knockdown was related to significant increase in DNA damage (with higher γH2AX and GADD45B levels) and downregulation of XLF and MRE11. Conclusions VIRMA has an oncogenic role in GCTs confirming our previous tissue-based study and is further involved in response to cisplatin by interfering with DNA repair. These data contribute to our better understanding of the emergence of cisplatin resistance in GCTs and support recent attempts to therapeutically target elements of the m6A writer complex.

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