The Role of <i>TP53</i> in Cisplatin Resistance in Mediastinal and Testicular Germ Cell Tumors
Germ cell tumors (GCTs) are considered to be highly curable; however, there are major differences in the outcomes related to histology and anatomical localization. GCTs originating from the testis are, overall, sensitive to platinum-based chemotherapy, whereas GCTs originating from the mediastinum s...
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| Main Authors: | , , , , , , , |
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| Format: | article |
| Language: | EN |
| Published: |
MDPI AG
2021
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| Subjects: | |
| Online Access: | https://doaj.org/article/e3ff7794ad124071bdac71a905542ee0 |
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| Summary: | Germ cell tumors (GCTs) are considered to be highly curable; however, there are major differences in the outcomes related to histology and anatomical localization. GCTs originating from the testis are, overall, sensitive to platinum-based chemotherapy, whereas GCTs originating from the mediastinum show a worse response, which remains largely unexplained. Here, we address the differences among GCTs from two different anatomical locations (testicular versus mediastinal/extragonadal), with a specific focus on the role of the P53 pathway. It was recently shown that GCTs with <i>TP53</i> mutations most often localize to the mediastinum. To elucidate the underlying mechanism, <i>TP53</i> knock-out lines were generated in cisplatin-sensitive and -resistant clones of the representative 2102Ep cell line (wild-type <i>TP53</i> testicular GCT) and NCCIT cell line (hemizygously mutated <i>TP53</i>, mutant <i>TP53</i> mediastinal GCT). The full knock-out of <i>TP53</i> in 2102Ep and resistant NCCIT resulted in an increase in cisplatin resistance, suggesting a contributing role for P53, even in NCCIT, in which P53 had been reported to be non-functional. In conclusion, these results suggest that <i>TP53</i> mutations contribute to the cisplatin-resistant phenotype of mediastinal GCTs and, therefore, are a potential candidate for targeted treatment. This knowledge provides a novel model system to elucidate the underlying mechanism of clinical behavior and possible alternative treatment of the <i>TP53</i> mutant and mediastinal GCTs. |
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