RIPK1 and RIPK3 – emerging targets in cancer?

  • Kerem Gurol
  • Suraj Shah
  • Alexei Degterev
Keywords: RIPK1, RIPK3

Abstract

Abstract: RIPK1 and RIPK3 are homologous Ser/Thr kinases, which act in concert within the necrosome complexes to initiate a sub-type of regulated necrosis, termed necroptosis. Necroptosis has gradually emerged as a highly clinically relevant form of necrosis, which can be targeted therapeutically. Besides necroptosis, RIPK1 and RIPK3 have been implicated in other pathophysiologically-relevant responses, including regulation of apoptosis and inflammation. More recently, it became evident that RIPK1/RIPK3 pathways may be systematically altered in cancers. Status of these pathways may provide a prognostic value, and therapeutic modulation of RIPK1/RIPK3 signaling may represent a new strategy against various forms of human cancer.

 

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References

Wegner KW, Saleh D, Degterev A. Complex Pathologic Roles of RIPK1 and RIPK3: Moving Beyond Necroptosis. Trends Pharmacol Sci. 2017;38(3):202-25. doi: 10.1016/j.tips.2016.12.005. PubMed PMID: 28126382; PMCID: PMC5325808.

Petrie EJ, Hildebrand JM, Murphy JM. Insane in the membrane: a structural perspective of MLKL function in necroptosis. Immunol Cell Biol. 2017;95(2):152-9. doi: 10.1038/icb.2016.125. PubMed PMID: 27999433.

Moriwaki K, Chan FK. The Inflammatory Signal Adaptor RIPK3: Functions Beyond Necroptosis. Int Rev Cell Mol Biol. 2017;328:253-75. doi: 10.1016/ bs.ircmb.2016.08.007. PubMed PMID: 28069136.

Kearney CJ, Martin SJ. An Inflammatory Perspective on Necroptosis. Mol Cell. 2017;65(6):965-73. doi: 10.1016/j.molcel.2017.02.024. PubMed PMID: 28306512.

Grootjans S, Vanden Berghe T, Vandenabeele P. Initiation and execution mechanisms of necroptosis: an overview. Cell Death Differ. 2017;24(7):1184-95. doi: 10.1038/cdd.2017.65. PubMed PMID: 28498367; PMCID: PMC5520172.

G a l l u z z i L , K e p p O , C h a n F K , K r o e m e r G . Necroptosis: Mechanisms and Relevance to Disease. Annu Rev Pathol. 2017;12:103-30. doi: 10.1146/ annurev-pathol-052016-100247. PubMed PMID: 27959630.

Brault M, Oberst A. Controlled detonation: evolution of necroptosis in pathogen defense. Immunol Cell Biol. 2017;95(2):131-6. doi: 10.1038/icb.2016.117. PubMed PMID: 27909314.

Arora D, Sharma PK, Siddiqui MH, Shukla Y. Necroptosis: Modules and molecular switches with therapeutic implications. Biochimie. 2017;137:35-45. doi: 10.1016/j.biochi.2017.02.015. PubMed PMID: 28263777.

Newton K, Manning G. Necroptosis and Inflammation. Annu Rev Biochem. 2016;85:743-63. doi: 10.1146/ annurev-biochem-060815-014830. PubMed PMID: 26865533.

Moriwaki K, Chan FK. Necroptosis-independent signaling by the RIP kinases in inflammation. Cell Mol Life Sci. 2016;73(11-12):2325-34. doi: 10.1007/ s00018-016-2203-4. PubMed PMID: 27048814; PMCID: PMC4889460.

Moreno-Gonzalez G, Vandenabeele P, Krysko DV. Necroptosis: A Novel Cell Death Modality and Its Potential Relevance for Critical Care Medicine. Am J Respir Crit Care Med. 2016;194(4):415-28. doi: 10.1164/rccm.201510-2106CI. PubMed PMID: 27285640.

Christofferson DE, Yuan J. Necroptosis as an alternative form of programmed cell death. Curr Opin Cell Biol. 2010;22(2):263-8. doi: 10.1016/ j.ceb.2009.12.003. PubMed PMID: 20045303; PMCID:

PMC2854308.

Declercq W, Vanden Berghe T Fau - Vandenabeele P,

PMCID: PMC5471631.

Bertrand MJ, Vandenabeele P. The Ripoptosome:

Vandenabeele P. RIP kinases at the crossroads of cell d e a t h d e c i s i o n i n t h e c y t o s o l . M o l C e l l .

death and survival(1097-4172 (Electronic)). 2011;43(3):323-5. doi: 10.1016/j.molcel.2011.07.007.

Tait SWG, Green DR. Caspase-independent cell PubMed PMID: 21816342.

death: leaving the set without the final cut. Oncogene. 25 Feoktistova M, Geserick P, Panayotova-Dimitrova D,

;27:6452. doi: 10.1038/onc.2008.311. Leverkus M. Pick your poison: the Ripoptosome, a cell

Vanden Berghe T, Hassannia B, Vandenabeele P. death platform regulating apoptosis and necroptosis.

An outline of necrosome triggers. Cell Mol Life Sci. Cell Cycle. 2012 ; 11 ( 3 ) : 460 - 7 . doi: 10 . 4161 /

;73(11-12):2137-52. doi: 10.1007/s00018- cc.11.3.19060. PubMed PMID: 22274400.

-2189-y. PubMed PMID: 27052312; PMCID: 26 Mocarski ES, Guo H, Kaiser WJ. Necroptosis:

PMC4887535. The Trojan horse in cell autonomous antiviral host

Vanlangenakker N, Vanden Berghe T, Vandenabeele defense. Virology. 2015;479-480:160-6. doi: 10.1016/

P. Many stimuli pull the necrotic trigger, an overview. j.virol.2015.03.016. PubMed PMID: 25819165;

Cell Death Differ. 2012;19(1):75-86. doi: 10.1038/ PMCID: PMC5115625.

cdd.2011.164. PubMed PMID: 22075985; PMCID: 27 Weinlich R, Oberst A, Beere HM, Green DR.

PMC3252835. Necroptosis in development, inflammation and

Li J, McQuade T, Siemer AB, Napetschnig J, Moriwaki disease. Nature reviews Molecular cell biology.

K, Hsiao YS, Damko E, Moquin D, Walz T, McDermott 2017;18(2):127-36. doi: 10.1038/nrm.2016.149.

A, Chan FK, Wu H. The RIP1/RIP3 necrosome forms PubMed PMID: 27999438.

a functional amyloid signaling complex required for 28 Zhao H, Jaffer T, Eguchi S, Wang Z, Linkermann A,

programmed necrosis. Cell. 2012;150(2):339-50. doi: Ma D. Role of necroptosis in the pathogenesis of

1016/j.cell.2012.06.019. PubMed PMID: 22817896; solid organ injury. Cell Death Dis. 2015;6:e1975. doi:

PMCID: PMC3664196. 10.1038/cddis.2015.316. PubMed PMID: 26583318;

Zhang J, Yang Y, He W, Sun L. Necrosome PMCID: PMC4670925.

c o r e m a c h i n e r y : M L K L . C e l l M o l L i f e S c i . 29 Zhou W, Yuan J. Necroptosis in health and diseases.

0 1 6 ; 7 3 ( 11 - 1 2 ) : 2 1 5 3 - 6 3 . d o i : 1 0 . 1 0 0 7 / Semin Cell Dev Biol. 2014;35:14-23. doi: 10.1016/

s00018-016-2190-5. PubMed PMID: 27048809. j.semcdb.2014.07.013. PubMed PMID: 25087983.

Green DR, Oberst A, Dillon CP, Weinlich R, Salvesen 30 Bruzzoni-Giovanelli H, Gonzalez JR, Sigaux F,

GS. RIPK-dependent necrosis and its regulation Villoutreix BO, Cayuela JM, Guilhot J, Preudhomme

by caspases: a mystery in five acts. Mol Cell. C, Guilhot F, Poyet JL, Rousselot P. Genetic

;44(1):9-16. doi: 10.1016/j.molcel.2011.09.003. polymorphisms associated with increased risk

PubMed PMID: 21981915; PMCID: PMC3192321. of developing chronic myelogenous leukemia.

Dondelinger Y, Darding M, Bertrand MJ, Walczak H. Oncotarget. 2015;6(34):36269-77. doi: 10.18632/

Poly-ubiquitination in TNFR1-mediated necroptosis. oncotarget.5915. PubMed PMID: 26474455; PMCID:

Cell Mol Life Sci. 2016;73(11-12):2165-76. doi: PMC4742176.

. 1007 / s 00018 - 016 - 2191 - 4 . Pub Med PMID: 31 Cerhan JR, Ansell SM, Fredericksen ZS, Kay NE,

; PMCID: PMC4887548. Liebow M, Call TG, Dogan A, Cunningham JM, Wang

Christofferson DE, Li Y, Hitomi J, Zhou W, Upperman AH, Liu-Mares W, Macon WR, Jelinek D, Witzig TE,

C, Zhu H, Gerber SA, Gygi S, Yuan J. A novel role for Habermann TM, Slager SL. Genetic variation in 1253

RIP1 kinase in mediating TNFalpha production. Cell immune and inflammation genes and risk of non-

Death Dis. 2012;3:e320. doi: 10.1038/cddis.2012.64. Hodgkin lymphoma. Blood. 2007;110(13):4455-63.

PubMed PMID: 22695613; PMCID: PMC3388236. doi: 10.1182/blood-2007-05-088682. PubMed PMID:

Najjar M, Saleh D, Zelic M, Nogusa S, Shah S, Tai A, 17827388; PMCID: PMC2234796.

Finger JN, Polykratis A, Gough PJ, Bertin J, Whalen M, 32 Geserick P, Wang J, Schilling R, Horn S, Harris PA,

Pasparakis M, Balachandran S, Kelliher M, Poltorak Bertin J, Gough PJ, Feoktistova M, Leverkus M.

A, Degterev A. RIPK1 and RIPK3 Kinases Promote Absence of RIPK3 predicts necroptosis resistance

Cell-Death-Independent Inflammation by Toll-like in malignant melanoma. Cell Death Dis. 2015;6:

Receptor 4. Immunity. 2016;45(1):46-59. doi: 10.1016/ e1884. doi: 10.1038/cddis.2015.240. PubMed PMID:

j.immuni.2016.06.007. PubMed PMID: 27396959; 26355347; PMCID: PMC4650439.

PMCID: PMC4956514. 33 Koo GB, Morgan MJ, Lee DG, Kim WJ, Yoon JH,

Saleh D, Najjar M, Zelic M, Shah S, Nogusa S, Koo JS, Kim SI, Kim SJ, Son MK, Hong SS, Levy

Polykratis A, Paczosa MK, Gough PJ, Bertin J, JM, Pollyea DA, Jordan CT, Yan P, Frankhouser D,

Whalen M, Fitzgerald KA, Slavov N, Pasparakis M, Nicolet D, Maharry K, Marcucci G, Choi KS, Cho H,

Balachandran S, Kelliher M, Mecsas J, Degterev A. Thorburn A, Kim YS. Methylation-dependent loss of

Kinase Activities of RIPK1 and RIPK3 Can Direct RIP3 expression in cancer represses programmed

IFN-beta Synthesis Induced by Lipopolysaccharide. necrosis in response to chemotherapeutics. Cell Res.

J Immunol. 2017;198(11):4435-47. doi: 10.4049/ 2015;25(6):707-25. doi: 10.1038/cr.2015.56. PubMed

jimmunol.1601717. PubMed PMID: 28461567; PMID: 25952668; PMCID: PMC4456623.

Nugues AL, El Bouazzati H, Hétuin D, Berthon C, 10.1002/cncr.28144.

Loyens A, Bertrand E, Jouy N, Idziorek T, Quesnel B. 42 He L, Peng K, Liu Y, Xiong J, Zhu F-f. Low expression

RIP3 is downregulated in human myeloid leukemia of mixed lineage kinase domain-like protein is

cells and modulates apoptosis and caspase- associated with poor prognosis in ovarian cancer

mediated p65/RelA cleavage. Cell Death &Amp; patients. OncoTargets and therapy. 2013;6:1539-43.

Disease. 2014;5:e1384. doi: 10.1038/cddis.2014.347. d o i : 1 0 . 2 1 4 7 / O T T. S 5 2 8 0 5 . P u b M e d P M I D :

https://www.nature.com/articles/cddis2014347-

PMC3817086.

supplementary-information.

Li X, Guo J, Ding AP, Qi WW, Zhang PH, Lv J, Qiu

Yang H, Ma Y, Chen G, Zhou H, Yamazaki T, Klein WS, Sun ZQ. Association of Mixed Lineage Kinase

C, Pietrocola F, Vacchelli E, Souquere S, Sauvat A, Domain-Like Protein Expression With Prognosis in

Zitvogel L, Kepp O, Kroemer G. Contribution of RIP3 Patients With Colon Cancer. Technol Cancer Res

and MLKL to immunogenic cell death signaling in Treat. 2017;16(4):428-34. doi: 10.1177/1533034

cancer chemotherapy. Oncoimmunology. 2016;5(6): 616655909. PubMed PMID: 27432118; PMCID:

e1149673. doi: 10.1080/2162402X.2016.1149673. PMC5616063.

PubMed PMID: 27471616; PMCID: PMC4938314. 44 Ruan J, Mei L, Zhu Q, Shi G, Wang H. Mixed lineage

Hockendorf U, Yabal M, Herold T, Munkhbaatar E, kinase domain-like protein is a prognostic biomarker

Rott S, Jilg S, Kauschinger J, Magnani G, Reisinger for cervical squamous cell cancer. International

F, Heuser M, Kreipe H, Sotlar K, Engleitner T, Rad R, Journal of Clinical and Experimental Pathology.

Weichert W, Peschel C, Ruland J, Heikenwalder M, 2015;8(11):15035-8. PubMed PMID: PMC4713627.

Spiekermann K, Slotta-Huspenina J, Gross O, Jost 45 Ertao Z, Jianhui C, Kang W, Zhijun Y, Hui W,

PJ. RIPK3 Restricts Myeloid Leukemogenesis by Chuangqi C, Changjiang Q, Sile C, Yulong H, Shirong

Promoting Cell Death and Differentiation of Leukemia C. Prognostic value of mixed lineage kinase domain-

Initiating Cells. Cancer Cell. 2016;30(1):75-91. like protein expression in the survival of patients with

doi: 10.1016/j.ccell.2016.06.002. PubMed PMID: gastric caner. Tumor Biology. 2016;37(10):13679-85.

doi: 10.1007/s13277-016-5229-1.

Moriwaki K, Bertin J, Gough PJ, Orlowski GM, Chan 46 Yang C, Li J, Yu L, Zhang Z, Xu F, Jiang L, Zhou X,

FK. Differential roles of RIPK1 and RIPK3 in TNF- He S. Regulation of RIP3 by the transcription factor

induced necroptosis and chemotherapeutic agent- Sp1 and the epigenetic regulator UHRF1 modulates

induced cell death. Cell Death &Amp; Disease. cancer cell necroptosis. Cell Death Dis. 2017;8(10):

;6:e1636. doi: 10.1038/cddis.2015.16. https://

e3084. doi: 10.1038/cddis.2017.483. PubMed PMID:

www.nature.com/articles/cddis201516-supplementary-

; PMCID: PMC5682651.

information.

Hitomi J, Christofferson DE, Ng A, Yao J, Degterev

Bozec D, Iuga AC, Roda G, Dahan S, Yeretssian A, Xavier RJ, Yuan J. Identification of a molecular

G. Critical function of the necroptosis adaptor signaling network that regulates a cellular necrotic

RIPK3 in protecting from intestinal tumorigenesis. cell death pathway. Cell. 2008;135(7):1311-23. doi:

Oncotarget. 2016;7(29):46384-400. doi: 10.18632/ 10.1016/j.cell.2008.10.044. PubMed PMID: 19109899;

oncotarget.10135. PubMed PMID: 27344176; PMCID: PMCID: PMC2621059.

PMC5216805. 48 McNamara CR, Ahuja R, Osafo-Addo AD, Barrows

Feng X, Song Q, Yu A, Tang H, Peng Z, Wang X. D, Kettenbach A, Skidan I, Teng X, Cuny GD,

Receptor-interacting protein kinase 3 is a predictor Gerber S, Degterev A. Akt Regulates TNFalpha

of survival and plays a tumor suppressive role in synthesis downstream of RIP1 kinase activation

colorectal cancer. Neoplasma. 2015;62(4):592-601. during necroptosis. PLoS One. 2013;8(3):e56576.

doi: 10 . 4149 / neo_ 2015 _ 071 . Pub Med PMID: doi: 10.1371/journal.pone.0056576. PubMed PMID:

23469174; PMCID: PMC3585731.

Liu P, Xu B, Shen W, Zhu H, Wu W, Fu Y, Chen H, 49 Yang Z, Jiang B, Wang Y, Ni H, Zhang J, Xia J,

Dong H, Zhu Y, Miao K, Xu W, Li J. Dysregulation Shi M, Hung LM, Ruan J, Mak TW, Li Q, Han J.

of TNFα-induced necroptotic signaling in chronic 2-HG Inhibits Necroptosis by Stimulating DNMT1-

lymphocytic leukemia: suppression of CYLD gene Dependent Hypermethylation of the RIP3 Promoter.

by LEF1. Leukemia. 2011;26:1293. doi: 10.1038/ Cell Rep. 2017 ; 19 ( 9 ) : 1846 - 57 . doi: 10 . 1016 /

leu.2011.357. https://www.nature.com/articles/

j.celrep.2017.05.012. PubMed PMID: 28564603.

leu2011357-supplementary-information.

Reynoso E, Liu H, Li L, Yuan AL, Chen S, Wang Z.

Colbert LE, Fisher SB, Hardy CW, Hall WA, Saka Thioredoxin-1 actively maintains the pseudokinase

B, Shelton JW, Petrova AV, Warren MD, Pantazides MLKL in a reduced state to suppress disulfide bond-

BG, Gandhi K, Kowalski J, Kooby DA, El-Rayes BF, dependent MLKL polymer formation and necroptosis.

Staley CA, Adsay NV, Curran WJ, Landry JC, Maithel J Biol Chem. 2017;292(42):17514-24. doi: 10.1074/

SK, Yu DS. Pronecrotic mixed lineage kinase domain- jbc.M117.799353. PubMed PMID: 28878015; PMCID:

like protein expression is a prognostic biomarker PMC5655526.

in patients with early-stage resected pancreatic 51 Schroeder A, Warnken U, Röth D, Klika KD, Vobis D,

adenocarcinoma. Cancer. 2013;119(17):3148-55. doi: Barnert A, Bujupi F, Oberacker T, Schnölzer M, Nicolay

JP, Krammer PH, Gülow K. Targeting Thioredoxin-1 by dimethyl fumarate induces ripoptosome-mediated cell

death. Scientific Reports. 2017;7:43168. doi: 10.1038/ WJ, Deshayes K, Dixit VM, Vucic D. IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB

activation, and TNFalpha-dependent apoptosis. Cell.

srep43168. https://www.nature.com/articles/srep43168

;131(4):669-81. doi: 10.1016/j.cell.2007.10.030.

- supplementary-information. PubMed PMID: 18022362.

Najjar M, Suebsuwong C, Ray SS, Thapa RJ, Maki 61 Vince JE, Wong WW, Khan N, Feltham R, Chau D,

JL, Nogusa S, Shah S, Saleh D, Gough PJ, Bertin Ahmed AU, Benetatos CA, Chunduru SK, Condon

J, Yuan J, Balachandran S, Cuny GD, Degterev SM, McKinlay M, Brink R, Leverkus M, Tergaonkar V,

A. Structure guided design of potent and selective Schneider P, Callus BA, Koentgen F, Vaux DL, Silke

ponatinib- based hybrid inhibitors for RIPK 1 . J. IAP antagonists target cIAP1 to induce TNFalpha-

Cell Rep. 2015; 10( 11): 1850- 60. doi: 10. 1016/ dependent apoptosis. Cell. 2007;131(4):682-93. doi:

j.celrep.2015.02.052. PubMed PMID: 25801024; 10.1016/j.cell.2007.10.037. PubMed PMID: 18022363.

PMCID: PMC4494889. 62 Fulda S. Smac Mimetics to Therapeutically Target

Li JX, Feng JM, Wang Y, Li XH, Chen XX, Su Y, Shen IAP Proteins in Cancer. Int Rev Cell Mol Biol.

YY, Chen Y, Xiong B, Yang CH, Ding J, Miao ZH. The 2017;330:157-69. doi: 10.1016/bs.ircmb.2016.09.004.

B-Raf(V600E) inhibitor dabrafenib selectively inhibits PubMed PMID: 28215531.

RIP3 and alleviates acetaminophen-induced liver 63 Olsson M, Zhivotovsky B. Caspases and cancer.

injury. Cell Death Dis. 2014;5:e1278. doi: 10.1038/ Cell Death Differ. 2011;18(9):1441-9. doi: 10.1038/

cddis.2014.241. PubMed PMID: 24901049; PMCID: cdd.2011.30. PubMed PMID: 21455218; PMCID:

PMC4611716. PMC3178435.

Feldmann F, Schenk B, Martens S, Vandenabeele 64 He GW, Gunther C, Thonn V, Yu YQ, Martini

P, F u l d a S . S o r a f e n i b i n h i b i t s t h e r a p e u t i c E, Buchen B, Neurath MF, Sturzl M, Becker C.

induction of necroptosis in acute leukemia cells. Regression of apoptosis-resistant colorectal tumors

Oncotarget. 2017;8(40):68208-20. doi: 10.18632/ by induction of necroptosis in mice. J Exp Med.

oncotarget.19919. PubMed PMID: 28978109; PMCID: 2017;214(6):1655-62. doi: 10.1084/jem.20160442.

PMC5620249. PubMed PMID: 28476895; PMCID: PMC5460989.

Fauster A, Rebsamen M, Huber KV, Bigenzahn JW, 65 Diao Y, Ma X, Min W, Lin S, Kang H, Dai Z,

Stukalov A, Lardeau CH, Scorzoni S, Bruckner M, Wang X, Zhao Y. Dasatinib promotes paclitaxel-

Gridling M, Parapatics K, Colinge J, Bennett KL, induced necroptosis in lung adenocarcinoma with

Kubicek S, Krautwald S, Linkermann A, Superti-Furga phosphorylated caspase-8 by c-Src. Cancer Lett.

G. A cellular screen identifies ponatinib and pazopanib 2016;379(1):12-23. doi: 10.1016/j.canlet.2016.05.003.

as inhibitors of necroptosis. Cell Death Dis. 2015;6: PubMed PMID: 27195913.

e1767. doi: 10.1038/cddis.2015.130. PubMed PMID: 66 Brumatti G, Ma C, Lalaoui N, Nguyen NY, Navarro M,

; PMCID: PMC4669708. Tanzer MC, Richmond J, Ghisi M, Salmon JM, Silke

Fulda S, Vucic D. Targeting IAP proteins for N, Pomilio G, Glaser SP, de Valle E, Gugasyan R,

therapeutic intervention in cancer. Nat Rev Drug Gurthridge MA, Condon SM, Johnstone RW, Lock

Discov. 2012;11(2):109-24. doi: 10.1038/nrd3627. R, Salvesen G, Wei A, Vaux DL, Ekert PG, Silke J.

PubMed PMID: 22293567. The caspase-8 inhibitor emricasan combines with

Bai L, Smith DC, Wang S. Small-molecule SMAC the SMAC mimetic birinapant to induce necroptosis

mimetics as new cancer therapeutics. Pharmacology and treat acute myeloid leukemia. Sci Transl Med.

& therapeutics. 2014;144(1):82-95. Epub 2014/05/21. 2016;8(339):339ra69. doi: 10.1126/scitranslmed.

doi: 10.1016/j.pharmthera.2014.05.007. PubMed aad3099. PubMed PMID: 27194727.

PMID: 24841289; PMCID: PMC4247261. 67 McCabe KE, Bacos K, Lu D, Delaney JR, Axelrod J,

Bertrand MJ, Milutinovic S, Dickson KM, Ho WC, Potter MD, Vamos M, Wong V, Cosford ND, Xiang R,

Boudreault A, Durkin J, Gillard JW, Jaquith JB, Morris Stupack DG. Triggering necroptosis in cisplatin and

SJ, Barker PA. cIAP1 and cIAP2 facilitate cancer cell IAP antagonist-resistant ovarian carcinoma. Cell Death

survival by functioning as E3 ligases that promote Dis. 2014;5:e1496. doi: 10.1038/cddis.2014.448.

RIP1 ubiquitination. Mol Cell. 2008;30(6):689-700. PubMed PMID: 25356865; PMCID: PMC4237265.

doi: 10.1016/j.molcel.2008.05.014. PubMed PMID: 68 Oliver Metzig M, Fuchs D, Tagscherer KE, Grone HJ,

Schirmacher P, Roth W. Inhibition of caspases primes

Petersen SL, Wang L, Yalcin-Chin A, Li L, Peyton colon cancer cells for 5-fluorouracil-induced TNF-

M, Minna J, Harran P, Wang X. Autocrine TNFalpha alpha-dependent necroptosis driven by RIP1 kinase

signaling renders human cancer cells susceptible and NF-kappaB. Oncogene. 2016;35(26):3399-409.

to Smac-mimetic-induced apoptosis. Cancer Cell. doi: 10.1038/onc.2015.398. PubMed PMID: 26522725.

;12(5):445-56. doi: 10.1016/j.ccr.2007.08.029. 69 Moriwaki K, Balaji S, Chan FK. Border Security: The

PubMed PMID: 17996648; PMCID: PMC3431210. Role of RIPK3 in Epithelium Homeostasis. Front Cell

Varfolomeev E, Blankenship JW, Wayson SM, Dev Biol. 2016;4:70. doi: 10.3389/fcell.2016.00070.

Fedorova AV, Kayagaki N, Garg P, Zobel K, Dynek PubMed PMID: 27446921; PMCID: PMC4923062.

JN, Elliott LO, Wallweber HJ, Flygare JA, Fairbrother 70 Moriwaki K, Balaji S, McQuade T, Malhotra N, Kang J,

Chan FK. The necroptosis adaptor RIPK3 promotes

injury-induced cytokine expression and tissue

j.celrep.2016.03.037. PubMed PMID: 27050509.

Yatim N, Jusforgues-Saklani H, Orozco S, Schulz

repair. Immunity. 2014;41(4):567-78. doi: 10.1016/ O, Barreira da Silva R, Reis e Sousa C, Green DR,

j.immuni.2014.09.016. PubMed PMID: 25367573; Oberst A, Albert ML. RIPK1 and NF-kappaB signaling

PMCID: PMC4220270. in dying cells determines cross-priming of CD8(+) T

Schneider AT, Gautheron J, Feoktistova M, Roderburg cells. Science. 2015;350(6258):328-34. doi: 10.1126/

C, Loosen SH, Roy S, Benz F, Schemmer P, Buchler science.aad0395. PubMed PMID: 26405229; PMCID:

MW, Nachbur U, Neumann UP, Tolba R, Luedde M, PMC4651449.

Zucman-Rossi J, Panayotova-Dimitrova D, Leverkus 80 Takemura R, Takaki H, Okada S, Shime H, Akazawa

M, Preisinger C, Tacke F, Trautwein C, Longerich T, T, Oshiumi H, Matsumoto M, Teshima T, Seya T. PolyI:

Vucur M, Luedde T. RIPK1 Suppresses a TRAF2- C-Induced, TLR3/RIP3-Dependent Necroptosis Backs

Dependent Pathway to Liver Cancer. Cancer Cell. Up Immune Effector-Mediated Tumor Elimination In

;31(1):94-109. doi: 10.1016/j.ccell.2016.11.009. Vivo. Cancer Immunol Res. 2015;3(8):902-14. doi:

PubMed PMID: 28017612. 10.1158/2326-6066.CIR-14-0219. PubMed PMID:

Van TM, Polykratis A, Straub BK, Kondylis 25898986.

V, Papadopoulou N, Pasparakis M. Kinase- 81 Schmidt SV, Seibert S, Walch-Ruckheim B, Vicinus

independent functions of RIPK1 regulate hepatocyte B, Kamionka EM, Pahne-Zeppenfeld J, Solomayer

survival and liver carcinogenesis. J Clin Invest. EF, Kim YJ, Bohle RM, Smola S. RIPK3 expression

;127(7):2662-77. doi: 10.1172/JCI92508. PubMed in cervical cancer cells is required for PolyIC-

PMID: 28628031; PMCID: PMC5490752. induced necroptosis, IL-1alpha release, and efficient

Loder S, Fakler M, Schoeneberger H, Cristofanon paracrine dendritic cell activation. Oncotarget.

S, Leibacher J, Vanlangenakker N, Bertrand MJ, 2015;6(11):8635-47. doi: 10.18632/oncotarget.3249.

Vandenabeele P, Jeremias I, Debatin KM, Fulda S. PubMed PMID: 25888634; PMCID: PMC4496172.

RIP1 is required for IAP inhibitor-mediated sensitization 82 Koks CA, Garg AD, Ehrhardt M, Riva M, Vandenberk

of childhood acute leukemia cells to chemotherapy- L, Boon L, De Vleeschouwer S, Agostinis P, Graf

induced apoptosis. Leukemia. 2012;26(5):1020-9. N, Van Gool SW. Newcastle disease virotherapy

Epub 2011/12/17. doi: 10.1038/leu.2011.353. PubMed induces long-term survival and tumor-specific immune

PMID: 22173242. memory in orthotopic glioma through the induction of

Tenev T, Bianchi K, Darding M, Broemer M, Langlais C, immunogenic cell death. Int J Cancer. 2015;136(5):

Wallberg F, Zachariou A, Lopez J, MacFarlane M, Cain E313-25. doi: 10.1002/ijc.29202. PubMed PMID:

K, Meier P. The Ripoptosome, a signaling platform that 25208916.

assembles in response to genotoxic stress and loss 83 Sachet M, Liang YY, Oehler R. The immune

of IAPs. Mol Cell. 2011;43(3):432-48. doi: 10.1016/ response to secondary necrotic cells. Apoptosis.

j.molcel.2011.06.006. PubMed PMID: 21737329. 2017 ; 22 ( 10 ) : 1189 - 204 . doi: 10 . 1007 / s 10495 -

Hannes S, Abhari BA, Fulda S. Smac mimetic 017-1413-z. PubMed PMID: 28861714; PMCID:

triggers necroptosis in pancreatic carcinoma cells PMC5630647.

when caspase activation is blocked. Cancer Lett. 84 Lalaoui N, Brumatti G. Relevance of necroptosis in

;380(1):31-8. Epub 2016/06/09. doi: 10.1016/ cancer. Immunol Cell Biol. 2017;95(2):137-45. doi:

j.canlet.2016.05.036. PubMed PMID: 27267809. 10.1038/icb.2016.120. PubMed PMID: 27922620.

Laukens B, Jennewein C, Schenk B, Vanlangenakker 85 Krysko O, Aaes TL, Kagan VE, D'Herde K, Bachert C,

N, Schier A, Cristofanon S, Zobel K, Deshayes K, Leybaert L, Vandenabeele P, Krysko DV. Necroptotic

Vucic D, Jeremias I, Bertrand MJ, Vandenabeele P, cell death in anti-cancer therapy. Immunol Rev.

Fulda S. Smac mimetic bypasses apoptosis resistance 2017;280(1):207-19. doi: 10.1111/imr.12583. PubMed

in FADD- or caspase-8-deficient cells by priming for PMID: 29027225.

tumor necrosis factor alpha-induced necroptosis. 86 Garg AD, Agostinis P. Cell death and immunity

Neoplasia (New York, NY). 2011;13(10):971-9. Epub in cancer: From danger signals to mimicry of

/10/27. PubMed PMID: 22028622; PMCID: pathogen defense responses. Immunol Rev.

PMC3201573. 2017;280(1):126-48. doi: 10.1111/imr.12574. PubMed

Biton S, Ashkenazi A. NEMO and RIP1 control cell fate PMID: 29027218.

in response to extensive DNA damage via TNF-alpha 87 Sun D, Zhao L, Lin J, Zhao Y, Zheng Y. Cationic

feedforward signaling. Cell. 2011;145(1):92-103. doi: liposome co-encapsulation of SMAC mimetic and

1016/j.cell.2011.02.023. PubMed PMID: 21458669. zVAD using a novel lipid bilayer fusion loaded with

Aaes TL, Kaczmarek A, Delvaeye T, De Craene MLKL-pDNA for tumour inhibition in vivo. Journal of

B, De Koker S, Heyndrickx L, Delrue I, Taminau drug targeting. 2018;26(1):45-54. Epub 2017/06/27.

J, Wiernicki B, De Groote P, Garg AD, Leybaert L, doi: 10.1080/1061186x.2017.1339192. PubMed PMID:

Grooten J, Bertrand MJ, Agostinis P, Berx G, Declercq 28649853.

W, Vandenabeele P, Krysko DV. Vaccination with 88 Bhatti IA, Abhari BA, Fulda S. Identification of

Necroptotic Cancer Cells Induces Efficient Anti-tumor a synergistic combination of Smac mimetic and

Immunity. Cell Rep. 2016;15(2):274-87. doi: 10.1016/ Bortezomib to trigger cell death in B-cell non-Hodgkin

lymphoma cells. Cancer Lett. 2017;405:63-72. activation. Cancer Discov. 2013;3(2):212-23. doi:

doi: 10.1016/j.canlet.2017.07.008. PubMed PMID: 10.1158/2159-8290.CD-12-0271. PubMed PMID:

23269702; PMCID: PMC3570610.

Rohde K, Kleinesudeik L, Roesler S, Lowe O, Heidler 97 Alharbi RA, Pandha HS, Simpson GR, Pettengell R,

J, Schroder K, Wittig I, Drose S, Fulda S. A Bak- Poterlowicz K, Thompson A, Harrington K, El-Tanani

dependent mitochondrial amplification step contributes M, Morgan R. Inhibition of HOX/PBX dimer formation

to Smac mimetic/glucocorticoid-induced necroptosis. leads to necroptosis in acute myeloid leukemia cells.

Cell Death Differ. 2017;24(1):83-97. doi: 10.1038/ Oncotarget. 2017;8(52):89566-79. doi: 10.18632/

cdd.2016.102. PubMed PMID: 27834956; PMCID: oncotarget.20023. PubMed PMID: 29163771; PMCID:

PMC5260489. PMC5685692.

Cekay MJ, Roesler S, Frank T, Knuth AK, Eckhardt 98 Xie Y, Zhu S, Zhong M, Yang M, Sun X, Liu J, Kroemer

I, Fulda S. Smac mimetics and type II interferon G, Lotze M, Zeh HJ, 3rd, Kang R, Tang D. Inhibition

synergistically induce necroptosis in various cancer of Aurora Kinase A Induces Necroptosis in Pancreatic

cell lines. Cancer Lett. 2017;410:228-37. Epub Carcinoma. Gastroenterology. 2017;153(5):1429-43

/09/20. doi: 10.1016/j.canlet.2017.09.002. e5. doi: 10.1053/j.gastro.2017.07.036. PubMed PMID:

PubMed PMID: 28923396. 28764929; PMCID: PMC5670014.

Tanzer MC, Khan N, Rickard JA, Etemadi N, Lalaoui 99 Chen L, Yuan Y, Kar S, Kanchi MM, Arora S, Kim

N, Spall SK, Hildebrand JM, Segal D, Miasari M, JE, Koh PF, Yousef E, Samy RP, Shanmugam MK,

Chau D, Wong WL, McKinlay M, Chunduru SK, Tan TZ, Shin SW, Arfuso F, Shen HM, Yang H, Goh

Benetatos CA, Condon SM, Vince JE, Herold BC, Park JI, Gaboury L, Lobie PE, Sethi G, Lim LH,

MJ, Silke J. Combination of IAP antagonist and Kumar AP. PPARgamma Ligand-induced Annexin A1

IFNgamma activates novel caspase-10- and RIPK1- Expression Determines Chemotherapy Response via

dependent cell death pathways. Cell Death Differ. Deubiquitination of Death Domain Kinase RIP in Triple

;24(3):481-91. Epub 2017/01/21. doi: 10.1038/ Negative Breast Cancers. Mol Cancer Ther. 2017. doi:

cdd.2016.147. PubMed PMID: 28106882; PMCID: 10.1158/1535-7163.MCT-16-0739. PubMed PMID:

PMC5344208. 28811325.

Jinesh GG, Chunduru S, Kamat AM. Smac mimetic 100 Zhang X, Kitatani K, Toyoshima M, Ishibashi M, Usui

enables the anticancer action of BCG-stimulated T, Minato J, Egiz M, Shigeta S, Fox T, Deering T,

neutrophils through TNF-alpha but not through Kester M, Yaegashi N. Ceramide Nanoliposomes

TRAIL and FasL. Journal of leukocyte biology. as a MLKL- Dependent, Necroptosis- Inducing,

;92(1):233-44. Epub 2012/04/21. doi: 10.1189/ Chemotherapeutic Reagent in Ovarian Cancer. Mol

jlb.1211623. PubMed PMID: 22517918; PMCID: Cancer Ther. 2018;17(1):50-9. Epub 2017/10/29. doi:

PMC3382315. 10.1158/1535-7163.mct-17-0173. PubMed PMID:

Bittner S, Knoll G, Ehrenschwender M. Hyperosmotic 29079707; PMCID: PMC5752574.

stress enhances cytotoxicity of SMAC mimetics. 101 Sonkusre P, Cameotra SS. Biogenic selenium

Cell Death Dis. 2017;8(8):e2967. doi: 10.1038/ nanoparticles induce ROS-mediated necroptosis

cddis.2017.355. PubMed PMID: 28771230; PMCID: in PC-3 cancer cells through TNF activation. J

PMC5596546. Nanobiotechnology. 2017;15(1):43. doi: 10.1186/

Beug ST, Beauregard CE, Healy C, Sanda T, St- s12951-017-0276-3. PubMed PMID: 28592284;

Jean M, Chabot J, Walker DE, Mohan A, Earl N, Lun X, Senger DL, Robbins SM, Staeheli P, Forsyth PA, Alain T, LaCasse EC, Korneluk RG. Smac mimetics synergize with immune checkpoint inhibitors to promote tumour immunity against glioblastoma. Nat Commun. 2017;8. doi: 10.1038/ncomms14278. PubMed PMID: 28198370; PMCID: PMC5330852.

Beug ST, Tang VA, LaCasse EC, Cheung HH, Beauregard CE, Brun J, Nuyens JP, Earl N, St-Jean M, Holbrook J, Dastidar H, Mahoney DJ, Ilkow C, Le Boeuf F, Bell JC, Korneluk RG. Smac mimetics and innate immune stimuli synergize to promote tumor death. Nat Biotechnol. 2014;32(2):182-90. doi: 10.1038/nbt.2806. PubMed PMID: 24463573; PMCID: PMC5030098.

Yang C, Davis JL, Zeng R, Vora P, Su X, Collins LI, Vangveravong S, Mach RH, Piwnica-Worms D , We i l b a e c h e r K N , F a c c i o R , N o v a c k D V. Antagonism of inhibitor of apoptosis proteins increases bone metastasis via unexpected osteoclast

PMCID: PMC5463494.

Sulkshane P, Teni T. BH 3 mimetic Obatoclax ( G X 1 5 - 0 7 0 ) m e d i a t e s m i t o c h o n d r i a l s t r e s s predominantly via MCL-1 inhibition and induces autophagy-dependent necroptosis in human oral cancer cells. Oncotarget. 2017;8(36):60060-79. doi: 10.18632/oncotarget.11085. PubMed PMID: 28947954; PMCID: PMC5601122.

Park S, Hatanpaa KJ, Xie Y, Mickey BE, Madden CJ, Raisanen JM, Ramnarain DB, Xiao G, Saha D, Boothman DA, Zhao D, Bachoo RM, Pieper RO, Habib AA. The Receptor Interacting Protein 1 Inhibits p53 Induction through NF-κB Activation and Confers a Worse Prognosis in Glioblastoma. Cancer Research. 2009;69(7):2809.

Wang Q, Chen W, Xu X, Li B, He W, Padilla MT, Jang JH, Nyunoya T, Amin S, Wang X, Lin Y. RIP1 potentiates BPDE-induced transformation in human bronchial epithelial cells through catalase- mediated suppression of excessive reactive oxygen

species. Carcinogenesis. 2013;34(9):2119-28. Epub 2013/05/02. doi: 10.1093/carcin/bgt143. PubMed PMID: 23633517; PMCID: PMC3765041.

Liu X, Zhou M, Mei L, Ruan J, Hu Q, Peng J, Su H, Liao H, Liu S, Liu W, Wang H, Huang Q, Li F, Li CY. Key roles of necroptotic factors in promoting tumor growth. Oncotarget. 2016;7(16):22219-33. Epub 2016/03/10. doi: 10.18632/oncotarget.7924. PubMed PMID: 26959742; PMCID: PMC5008357.

Seifert L, Werba G, Tiwari S, Giao Ly NN, Alothman S, Alqunaibit D, Avanzi A, Barilla R, Daley D, Greco SH, Torres-Hernandez A, Pergamo M, Ochi A, Zambirinis CP, Pansari M, Rendon M, Tippens D, Hundeyin M, Mani VR, Hajdu C, Engle D, Miller G. The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression. Nature. 2016;532(7598):245-9. Epub 2016/04/07.

doi: 10.1038/nature17403. PubMed PMID: 27049944; PMCID: PMC4833566.

Xin J, You D, Breslin P, Li J, Zhang J, Wei W, Cannova J, Volk A, Gutierrez R, Xiao Y, Ni A, Ng G, Schmidt R, Xia Z, Pan J, Chen H, Patel MM, Kuo PC, Nand S, Kini AR, Zhang J, Chen J, Zhu J, Zhang J. Sensitizing acute myeloid leukemia cells to induced differentiation by inhibiting the RIP1/RIP3 pathway. Leukemia. 2017;31(5):1154-65. Epub 2016/10/18. doi: 10.1038/ leu.2016.287. PubMed PMID: 27748372; PMCID: PMC5457287.

Ofengeim D, Yuan J. Regulation of RIP1 kinase signalling at the crossroads of inflammation and cell death. Nature reviews Molecular cell biology. 2013;14(11):727-36. Epub 2013/10/17. doi: 10.1038/ nrm3683. PubMed PMID: 24129419.

Strilic B, Yang L, Albarrán-Juárez J, Wachsmuth L, Han K, Müller UC, Pasparakis M, Offermanns S. Tumour-cell-induced endothelial cell necroptosis via death receptor 6 promotes metastasis. Nature. 2016;536:215. doi: 10.1038/nature19076. https://www. nature.com/articles/nature19076 - supplementary- information.

Hanggi K, Vasilikos L, Valls AF, Yerbes R, Knop J, Spilgies LM, Rieck K, Misra T, Bertin J, Gough PJ, Schmidt T, de Almodovar CR, Wong WW. RIPK1/ RIPK3 promotes vascular permeability to allow tumor cell extravasation independent of its necroptotic function. Cell Death Dis. 2017;8(2):e2588. doi:

1038/cddis.2017.20. PubMed PMID: 28151480; PMCID: PMC5386469.

Hoglen NC, Chen LS, Fisher CD, Hirakawa BP, Groessl T, Contreras PC. Characterization of IDN-6556 (3-[2-(2-tert-butyl-phenylaminooxalyl)- amino]-propionylamino]-4-oxo-5-(2,3,5,6-te trafluoro- phenoxy)-pentanoic acid): a liver-targeted caspase inhibitor. J Pharmacol Exp Ther. 2004;309(2):634-40. doi: 10. 1124/ jpet. 103. 062034. Pub Med PMID:

Ueno Y, Ohmi T, Yamamoto M, Kato N, Moriguchi Y, Kojima M, Shimozono R, Suzuki S, Matsuura T, Eda

H. Orally-administered caspase inhibitor PF-03491390 is retained in the liver for prolonged periods with low systemic exposure, exerting a hepatoprotective effect against alpha-fas-induced liver injury in a mouse model. J Pharmacol Sci. 2007;105(2):201-5. PubMed PMID: 17928737.

Lohmann C, Muschaweckh A, Kirschnek S, Jennen L, Wagner H, Hacker G. Induction of tumor cell apoptosis or necrosis by conditional expression of cell death proteins: analysis of cell death pathways and in vitro immune stimulatory potential. J Immunol. 2009;182(8):4538-46. doi: 10.4049/jimmunol.0803989.

PubMed PMID: 19342627.

Brouckaert G, Kalai M, Krysko DV, Saelens X, Vercammen D, Ndlovu MN, Haegeman G, D'Herde K, Vandenabeele P. Phagocytosis of necrotic cells by macrophages is phosphatidylserine dependent and does not induce inflammatory cytokine production. Mol Biol Cell. 2004;15(3):1089-100. doi: 10.1091/mbc. E03-09-0668. PubMed PMID: 14668480; PMCID: PMC363082.

Gong YN, Guy C, Olauson H, Becker JU, Yang M , F i t z g e r a l d P, L i n k e r m a n n A , G r e e n D R . ESCRT-III Acts Downstream of MLKL to Regulate Necroptotic Cell Death and Its Consequences. Cell. 2017; 169( 2): 286- 300 e16. doi: 10. 1016/ j.cell.2017.03.020. PubMed PMID: 28388412; PMCID: PMC5443414.

Kearney CJ, Cullen SP, Tynan GA, Henry CM, Clancy D, Lavelle EC, Martin SJ. Necroptosis suppresses inflammation via termination of TNF- or LPS-induced cytokine and chemokine production. Cell Death Differ. 2015;22(8):1313-27. doi: 10.1038/cdd.2014.222. PubMed PMID: 25613374; PMCID: PMC4495357.

Published
2018-11-08
How to Cite
Gurol, K., Shah, S., & Degterev, A. (2018). RIPK1 and RIPK3 – emerging targets in cancer?. <font Color="white">Molecular and Cellular Therapies</Font&gt;, 2018(1), 1-13. https://doi.org/10.26781/2052-8426-2018-03
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Research Article