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Updated: Apr 12, 2026
Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
Published on: August 7, 2018
Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to
Gi-Bang Koo1, Michael J Morgan2, Da-Gyum Lee3
11] Department of Biochemistry, Ajou University School of Medicine, Suwon 443-380, Korea [2] Department of Biomedical Sciences, Graduate School, Ajou University, Suwon 443-380, Korea.
Abstract:
Receptor-interacting protein kinase-3 (RIP3 or RIPK3) is an essential part of the cellular machinery that executes "programmed" or "regulated" necrosis. Here we show that programmed necrosis is activated in response to many chemotherapeutic agents and contributes to chemotherapy-induced cell death. However, we show that RIP3 expression is often silenced in cancer cells due to genomic methylation near its transcriptional start site, thus RIP3-dependent activation of MLKL and downstream programmed necrosis during chemotherapeutic death is largely repressed. Nevertheless, treatment with hypomethylating agents restores RIP3 expression, and thereby promotes sensitivity to chemotherapeutics in a RIP3-dependent manner. RIP3 expression is reduced in tumors compared to normal tissue in 85% of breast cancer patients, suggesting that RIP3 deficiency is positively selected during tumor growth/development. Since hypomethylating agents are reasonably well-tolerated in patients, we propose that RIP3-deficient cancer patients may benefit from receiving hypomethylating agents to induce RIP3 expression prior to treatment with conventional chemotherapeutics.
Insights
Receptor-interacting protein kinase-3 (RIP3) enables programmed necrosis, a cell death pathway often suppressed in cancers. Restoring RIP3 expression with hypomethylating agents may enhance chemotherapy effectiveness in RIP3-deficient tumors.
Area of Science:
- Molecular Biology
- Oncology
- Cell Death Pathways
Background:
- Receptor-interacting protein kinase-3 (RIP3) mediates programmed necrosis, a crucial cell death mechanism.
- Programmed necrosis is activated by various chemotherapeutic agents and contributes to treatment-induced cell death.
- Cancer cells frequently exhibit silenced RIP3 expression due to epigenetic modifications, hindering chemotherapy efficacy.
Purpose of the Study:
- To investigate the role of RIP3 in chemotherapy-induced cell death.
- To determine the impact of RIP3 silencing on cancer cell sensitivity to chemotherapeutics.
- To explore the therapeutic potential of restoring RIP3 expression in cancer treatment.
Main Methods:
- Analysis of RIP3 expression in cancer cells and patient tumor samples.
- Investigation of RIP3 silencing mechanisms, including genomic methylation.
- Assessment of programmed necrosis induction and cell death following chemotherapeutic treatment.
- Evaluation of hypomethylating agents for their ability to restore RIP3 expression and enhance chemosensitivity.
Main Results:
- Programmed necrosis is activated by chemotherapeutic agents and contributes to cell death.
- RIP3 expression is frequently silenced in cancer cells via methylation, repressing RIP3-dependent necrosis.
- Treatment with hypomethylating agents successfully restores RIP3 expression.
- Restored RIP3 expression enhances cancer cell sensitivity to chemotherapeutics in a RIP3-dependent manner.
- RIP3 expression is significantly reduced in 85% of breast cancer patients' tumors compared to normal tissue.
Conclusions:
- RIP3-mediated programmed necrosis is a key pathway in chemotherapy-induced cell death.
- Epigenetic silencing of RIP3 contributes to chemoresistance in cancer.
- Hypomethylating agents can overcome RIP3 silencing, resensitizing tumors to chemotherapy.
- RIP3 deficiency is selected for during tumor development, suggesting a therapeutic window for hypomethylating agents in RIP3-low cancers.
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