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Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Cell+Res 2015 ; 25 (6): 707-25 Nephropedia Template TP
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Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics #MMPMID25952668
Koo GB; Morgan MJ; Lee DG; Kim WJ; Yoon JH; Koo JS; Kim SI; Kim SJ; Son MK; Hong SS; Levy JMM; Pollyea DA; Jordan CT; Yan P; Frankhouser D; Nicolet D; Maharry K; Marcucci G; Choi KS; Cho H; Thorburn A; Kim YS
Cell Res 2015[Jun]; 25 (6): 707-25 PMID25952668show ga
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.