Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics

Gi Bang Koo, Michael J. Morgan, Da Gyum Lee, Woo Jung Kim, Jung Ho Yoon, JaSeung Koo, Seung Il Kim, Soo Jung Kim, Mi Kwon Son, Soon Sun Hong, Jean M.Mulcahy Levy, Daniel A. Pollyea, Craig T. Jordan, Pearlly Yan, David Frankhouser, Deedra Nicolet, Kati Maharry, Guido Marcucci, Kyeong Sook Choi, Hyeseong ChoAndrew Thorburn, You Sun Kim

Research output: Contribution to journalArticle

100 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)707-725
Number of pages19
JournalCell Research
Volume25
Issue number6
DOIs
Publication statusPublished - 2015 Jun 4

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Methylation
Necrosis
Neoplasms
Receptor-Interacting Protein Serine-Threonine Kinases
Growth and Development
Protein Kinases
Cell Death
Breast Neoplasms
Drug Therapy
Therapeutics

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

Koo, Gi Bang ; Morgan, Michael J. ; Lee, Da Gyum ; Kim, Woo Jung ; Yoon, Jung Ho ; Koo, JaSeung ; Kim, Seung Il ; Kim, Soo Jung ; Son, Mi Kwon ; Hong, Soon Sun ; Levy, Jean M.Mulcahy ; Pollyea, Daniel A. ; Jordan, Craig T. ; Yan, Pearlly ; Frankhouser, David ; Nicolet, Deedra ; Maharry, Kati ; Marcucci, Guido ; Choi, Kyeong Sook ; Cho, Hyeseong ; Thorburn, Andrew ; Kim, You Sun. / Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics. In: Cell Research. 2015 ; Vol. 25, No. 6. pp. 707-725.
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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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Koo, GB, Morgan, MJ, Lee, DG, Kim, WJ, Yoon, JH, Koo, J, 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 2015, 'Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics', Cell Research, vol. 25, no. 6, pp. 707-725. https://doi.org/10.1038/cr.2015.56

Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics. / Koo, Gi Bang; Morgan, Michael J.; Lee, Da Gyum; Kim, Woo Jung; Yoon, Jung Ho; Koo, JaSeung; Kim, Seung Il; Kim, Soo Jung; Son, Mi Kwon; Hong, Soon Sun; Levy, Jean M.Mulcahy; Pollyea, Daniel A.; Jordan, Craig T.; Yan, Pearlly; Frankhouser, David; Nicolet, Deedra; Maharry, Kati; Marcucci, Guido; Choi, Kyeong Sook; Cho, Hyeseong; Thorburn, Andrew; Kim, You Sun.

In: Cell Research, Vol. 25, No. 6, 04.06.2015, p. 707-725.

Research output: Contribution to journalArticle

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AU - Koo, Gi Bang

AU - Morgan, Michael J.

AU - Lee, Da Gyum

AU - Kim, Woo Jung

AU - Yoon, Jung Ho

AU - Koo, JaSeung

AU - Kim, Seung Il

AU - Kim, Soo Jung

AU - Son, Mi Kwon

AU - Hong, Soon Sun

AU - Levy, Jean M.Mulcahy

AU - Pollyea, Daniel A.

AU - Jordan, Craig T.

AU - Yan, Pearlly

AU - Frankhouser, David

AU - Nicolet, Deedra

AU - Maharry, Kati

AU - Marcucci, Guido

AU - Choi, Kyeong Sook

AU - Cho, Hyeseong

AU - Thorburn, Andrew

AU - Kim, You Sun

PY - 2015/6/4

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N2 - 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.

AB - 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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