Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics
| العنوان: | Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics |
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| المؤلفون: | Soo Jung Kim, You-Sun Kim, Andrew Thorburn, Hyeseong Cho, Daniel A. Pollyea, Gi Bang Koo, Seung Il Kim, Kyeong Sook Choi, Michael J. Morgan, Soon-Sun Hong, Deedra Nicolet, Kati Maharry, Ja Seung Koo, Mi Kwon Son, Da Gyum Lee, Guido Marcucci, Jung Ho Yoon, Woo-Jung Kim, Jean M. Mulcahy Levy, David Frankhouser, Craig T. Jordan, Pearlly S. Yan |
| المصدر: | Cell Research. 25:707-725 |
| بيانات النشر: | Springer Science and Business Media LLC, 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Programmed cell death, Necrosis, Cell Survival, medicine.medical_treatment, Mice, Nude, Breast Neoplasms, Biology, Mice, Structure-Activity Relationship, Breast cancer, Antineoplastic Combined Chemotherapy Protocols, Tumor Cells, Cultured, medicine, Animals, Humans, Molecular Biology, Mice, Inbred BALB C, Chemotherapy, Dose-Response Relationship, Drug, Cancer, Cell Biology, Methylation, DNA Methylation, medicine.disease, Xenograft Model Antitumor Assays, Receptor-Interacting Protein Serine-Threonine Kinases, DNA methylation, Immunology, Cancer cell, Cancer research, Original Article, Female, medicine.symptom |
| الوصف: | 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. |
| تدمد: | 1748-7838 1001-0602 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::44befffa94a6d7f971c0502002e4fe02Test https://doi.org/10.1038/cr.2015.56Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....44befffa94a6d7f971c0502002e4fe02 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17487838 10010602 |
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