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Comparative Analysis of the Transcriptomic Response to Cisplatin in Drug-Sensitive and Drug-Resistant Testicular Germ
Mehwish Wahid Khan1, Doha Shokry1, Raya I Boyd1
1Department of Comparative Biosciences, University of Illinois Urbana-Champaign, Urbana, IL 61802, USA.
Abstract:
Background/Objectives: Testicular germ cell tumors (TGCTs) are uniquely curable with cisplatin-based therapies even when widely metastatic; however, cisplatin resistance does occur, resulting in very poor prognosis. The mechanisms to explain TGCT hypersensitivity to cisplatin and mechanisms of resistance are not well-understood. Methods: The global transcriptional response to acute cisplatin treatment (24 h after a 6 h pulse of cisplatin) was assessed in three parental embryonal carcinoma TGCT cells lines compared to multiple isogenic, stable, cisplatin-resistant clonal lines from these parental cells. Results: Cisplatin treatment of parental cells consistently showed a more robust overall transcriptional response to cisplatin compared to their cisplatin-resistant cellular counterparts for a common set of genes and pathways including the upregulation of genes associated with histone modifications and p53, EMT, and KRAS signaling and the downregulation of genes normally upregulated by MYC. Focusing on genes exclusively altered in parental cells revealed upregulated genes known to be induced by p53 and downregulated by MYC and the transferrin receptor, TFRC1. Several of these p53/MYC/TFRC1 targets were associated with a higher instance of disease-free survival in a cohort of TGCT patients. Conclusions: Cisplatin resistance in TGCT cells is associated with a diminished alteration in cisplatin-responsive genes, especially genes known to be regulated by p53, MYC and TFRC1, that may be linked to cisplatin hypersensitivity and survival in TGCTs.
Insights
Testicular germ cell tumors (TGCTs) show unique cisplatin sensitivity. Cisplatin resistance in TGCTs is linked to reduced gene expression changes, particularly those involving p53, MYC, and TFRC1, impacting patient survival.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Testicular germ cell tumors (TGCTs) are highly curable with cisplatin therapy.
- Cisplatin resistance in TGCTs leads to poor prognosis.
- Mechanisms of TGCT cisplatin hypersensitivity and resistance are poorly understood.
Purpose of the Study:
- To investigate the global transcriptional response to cisplatin in TGCT cells.
- To compare gene expression patterns between cisplatin-sensitive and resistant TGCT cell lines.
- To identify molecular mechanisms underlying cisplatin resistance in TGCTs.
Main Methods:
- Assessed global transcriptional response to cisplatin in parental and isogenic resistant TGCT cell lines.
- Analyzed gene and pathway alterations after acute cisplatin exposure.
- Compared transcriptional profiles between sensitive and resistant cell lines.
Main Results:
- Parental TGCT cells exhibited a more robust transcriptional response to cisplatin than resistant cells.
- Upregulated genes in sensitive cells included those related to histone modifications, p53, EMT, and KRAS signaling.
- Downregulated genes in sensitive cells included those normally upregulated by MYC and the transferrin receptor (TFRC1).
- Specific p53/MYC/TFRC1 targets were associated with improved disease-free survival in TGCT patients.
Conclusions:
- Cisplatin resistance in TGCTs is associated with a blunted transcriptional response to the drug.
- Diminished alterations in p53, MYC, and TFRC1-regulated genes may contribute to cisplatin resistance.
- These gene expression changes might be linked to both cisplatin hypersensitivity and survival outcomes in TGCT patients.
