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Epigenetic Inactivation of RIPK3-Dependent Necroptosis Augments Cisplatin Chemoresistance in Human Osteosarcoma
Aditya Sharma1, Daniel Pettee1, Christine Mella1
1Division of Hematology Oncology, Akron Children's Hospital, One Perkins Square, Akron, OH 44308, USA.
Abstract:
Osteosarcoma (OS) is the most common primary bone malignancy in children and adolescents. Unfortunately, drug resistance limits the efficacy of chemotherapeutic treatment and compromises therapeutic outcomes in a substantial proportion of cases. Aberrant CpG island methylation-associated transcriptional silencing contributes to chemoresistance in pediatric solid tumors. Here, using whole-genome DNA methylation screening on 16 human primary OS specimens, we identify receptor interacting protein kinase-3 (RIPK3), a molecular regulator of the necroptosis programmed cell death pathway, as a gene target of aberrant CpG methylation and demonstrate its role in human OS chemoresistance. We validated these findings via enforced expression and DsiRNA silencing, and evaluated the role of RIPK3 in cisplatin chemosensitivity and necroptosis activation through MLKL phosphorylation. We found that CpG island methylation results in RIPK3 silencing in primary human OS samples and cell lines. Enforced RIPK3 expression significantly enhanced cisplatin cytotoxicity in OS cells and DsiRNA knockdown reversed the cisplatin-sensitive phenotype. In cells with enforced RIPK3 expression, cisplatin treatment significantly increased phosphorylation of both RIPK3 and its target, MLKL, indicative of induction of necroptosis. Here, we identify RIPK3 as an important mediator of chemoresistance in OS and a potential pharmacologic target to improve chemotherapy efficacy in drug-resistant tumors.
Insights
Aberrant methylation silences RIPK3, a key protein in programmed cell death, leading to chemoresistance in osteosarcoma (OS). Restoring RIPK3 enhances chemotherapy effectiveness in drug-resistant OS tumors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Osteosarcoma (OS) is a common pediatric bone cancer.
- Chemotherapy resistance significantly impacts treatment outcomes in OS.
- Aberrant DNA methylation is implicated in chemoresistance in pediatric solid tumors.
Purpose of the Study:
- To identify genes epigenetically silenced by aberrant CpG island methylation in osteosarcoma.
- To investigate the role of receptor interacting protein kinase-3 (RIPK3) in chemoresistance and necroptosis in OS.
- To evaluate RIPK3 as a potential therapeutic target for overcoming drug resistance in OS.
Main Methods:
- Whole-genome DNA methylation screening of 16 human primary OS specimens.
- Validation of RIPK3 methylation and expression in OS cell lines.
- Functional studies involving enforced RIPK3 expression and DsiRNA silencing.
- Assessment of RIPK3 and MLKL phosphorylation in response to cisplatin treatment.
Main Results:
- Aberrant CpG island methylation was identified to silence RIPK3 in primary OS samples and cell lines.
- Enforced RIPK3 expression increased cisplatin-induced cytotoxicity in OS cells.
- RIPK3 knockdown reversed cisplatin sensitivity.
- Cisplatin treatment induced RIPK3 and MLKL phosphorylation, indicating necroptosis activation.
Conclusions:
- RIPK3 is epigenetically silenced in osteosarcoma, contributing to chemoresistance.
- Restoring RIPK3 expression enhances sensitivity to cisplatin chemotherapy.
- RIPK3 is a potential pharmacologic target to improve chemotherapy efficacy in drug-resistant osteosarcoma.
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