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.
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Acknowledgements
We thank Jiahuai Han for RIP3−/− MEFs. This work was supported by the Basic Science Research Program of the National Research Foundation of Korea (NRF) and Ministry of Education, Science, and Technology of Korea (2011-0030043 and 2014R1A2A1A11052951) to Y-S Kim.
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( Supplementary information is linked to the online version of the paper on the Cell Research website.)
Supplementary information
Supplementary information, Figure S1
Expression of RIP3 is essential for TNF-induced necrotic cell death. (PDF 557 kb)
Supplementary information, Figure S2
RIP3 expression sensitizes to DNA-damaging agents. (PDF 663 kb)
Supplementary information, Figure S3
RIP3 potentiates sustained JNK activity by DNA-damaging agents. (PDF 370 kb)
Supplementary information, Figure S4
Inhibition of programmed necrosis and RIP3 kinase activity impedes cell death by DNA-damaging agents. (PDF 635 kb)
Supplementary information, Figure S5
Non-cancer cells and normal tissues express RIP3 (PDF 436 kb)
Supplementary information, Figure S6
RIP3 expression is inversely correlated with genomic methylation. (PDF 739 kb)
Supplementary information, Figure S7
RIP3 expression is inversely correlated with expression of DNMT1. (PDF 486 kb)
Supplementary information, Figure S8
RIP3 expression is inversely correlated with genomic methylation in AML patients. (PDF 476 kb)
Supplementary information, Figure S9
RIP3 expression highly reduced in breast cancer tumors compared to non-tumor tissue from matched breast cancer patients. (PDF 502 kb)
Supplementary information, Figure S10
Hypomethylating agents restore TNF-induced necrotic cell death in RIP3-deficient cell types. (PDF 544 kb)
Supplementary information, Figure S11
Hypomethylating agent-induced sensitization to TNF-induced necrotic cell death is dependent on the induction of RIP3 expression. (PDF 639 kb)
Supplementary information, Figure S12
Restoration of RIP3 by hypomethylating agents enhances sensitivity to multiple chemotherapeutic agents. (PDF 720 kb)
Supplementary information, Figure S13
Restoration of RIP3 by hypomethylating agents enhances sensitivity to multiple chemotherapeutic agents. (PDF 612 kb)
Supplementary information, Figure S14
Hypomethylating agent-induced sensitization to chemotherapeutic-induced necrotic cell death is dependent on the induction of RIP3 expression. (PDF 463 kb)
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Koo, GB., Morgan, M., Lee, DG. et al. Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics. Cell Res 25, 707–725 (2015). https://doi.org/10.1038/cr.2015.56
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DOI: https://doi.org/10.1038/cr.2015.56
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