期刊
CELL RESEARCH
卷 25, 期 6, 页码 707-725出版社
INST BIOCHEMISTRY & CELL BIOLOGY
DOI: 10.1038/cr.2015.56
关键词
RIP3 (RIPK3); MLKL; programmed necrosis; chemotherapy; hypomethylating agents
类别
资金
- National Research Foundation of Korea (NRF)
- Ministry of Education, Science, and Technology of Korea [2011-0030043, 2014R1A2A1A11052951]
- National Research Foundation of Korea [2014R1A2A1A11052951] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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