RIPK3 upregulation confers robust proliferation and collateral cystine-dependence on breast cancer recurrence.

Adaptor Proteins, Signal Transducing / metabolism Animals Cell Proliferation / drug effects Cystine / metabolism Epigenesis, Genetic / drug effects Female Gene Expression Regulation, Neoplastic / drug effects Mammary Neoplasms, Animal / genetics Mitosis / drug effects Neoplasm Recurrence, Local / genetics Piperazines / pharmacology Receptor-Interacting Protein Serine-Threonine Kinases / genetics Signal Transduction / drug effects Transcriptome / genetics Tumor Stem Cell Assay Tumor Suppressor Protein p53 / metabolism Up-Regulation / drug effects YAP-Signaling Proteins

Journal

Cell death and differentiation
ISSN: 1476-5403
Titre abrégé: Cell Death Differ
Pays: England
ID NLM: 9437445

Informations de publication

Date de publication:
07 2020
Historique:
received: 19 03 2019
accepted: 14 01 2020
revised: 13 01 2020
pubmed: 29 1 2020
medline: 23 9 2021
entrez: 29 1 2020
Statut: ppublish

Résumé

The molecular and genetic basis of tumor recurrence is complex and poorly understood. RIPK3 is a key effector in programmed necrotic cell death and, therefore, its expression is frequently suppressed in primary tumors. In a transcriptome profiling between primary and recurrent breast tumor cells from a murine model of breast cancer recurrence, we found that RIPK3, while absent in primary tumor cells, is dramatically reexpressed in recurrent breast tumor cells by an epigenetic mechanism. Unexpectedly, we found that RIPK3 knockdown in recurrent tumor cells reduced clonogenic growth, causing cytokinesis failure, p53 stabilization, and repressed the activities of YAP/TAZ. These data uncover a surprising role of the pro-necroptotic RIPK3 kinase in enabling productive cell cycle during tumor recurrence. Remarkably, high RIPK3 expression also rendered recurrent tumor cells exquisitely dependent on extracellular cystine and undergo necroptosis upon cystine deprivation. The induction of RIPK3 in recurrent tumors unravels an unexpected mechanism that paradoxically confers on tumors both growth advantage and necrotic vulnerability, providing potential strategies to eradicate recurrent tumors.

Identifiants

DOI: 10.1038/s41418-020-0499-y PMID: 31988496 PMC: PMC7308288
pubmed: 31988496
doi: 10.1038/s41418-020-0499-y
pii: 10.1038/s41418-020-0499-y
pmc: PMC7308288
doi:

Substances chimiques

Adaptor Proteins, Signal Transducing 0
Piperazines 0
Tumor Suppressor Protein p53 0
Wwtr1 protein, mouse 0
YAP-Signaling Proteins 0
Yap1 protein, mouse 0
erastin 0
Cystine 48TCX9A1VT
Receptor-Interacting Protein Serine-Threonine Kinases EC 2.7.11.1
Ripk3 protein, mouse EC 2.7.11.1

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

2234-2247

Subventions

Organisme : NCI NIH HHS
ID : P30 CA014236
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM124062
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS111588
Pays : United States

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Auteurs

Chao-Chieh Lin (CC)

Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, 27710, USA.
Center for Genomic and Computational Biology, Duke University School of Medicine, Durham, NC, 27710, USA.
ORCID: 0000-0001-5890-9004

Nathaniel W Mabe (NW)

Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27710, USA.
ORCID: 0000-0003-2675-652X

Yi-Tzu Lin (YT)

Division Pediatric Hematology-Oncology, Duke University School of Medicine, Durham, NC, 27710, USA.

Wen-Hsuan Yang (WH)

Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, 27710, USA.
Center for Genomic and Computational Biology, Duke University School of Medicine, Durham, NC, 27710, USA.
Department of Biochemistry, Duke University School of Medicine, Durham, NC, 27710, USA.
ORCID: 0000-0001-5780-6839

Xiaohu Tang (X)

Department of Biological Sciences, Michigan Technological University, Houghton, MI, 49931, USA.

Lisa Hong (L)

Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, Baltimore, MD, 21250, USA.

Tianai Sun (T)

Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, 27710, USA.
Center for Genomic and Computational Biology, Duke University School of Medicine, Durham, NC, 27710, USA.

Jeremy Force (J)

Duke Cancer Institute, Duke University School of Medicine, Durham, NC, 27710, USA.

Jeffrey R Marks (JR)

Department of Surgery and Division of Surgical Sciences, Duke University School of Medicine, Durham, NC, 27710, USA.

Tso-Pang Yao (TP)

Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27710, USA.

James V Alvarez (JV)

Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27710, USA.

Jen-Tsan Chi (JT)

Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, 27710, USA. jentsan.chi@duke.edu.
Center for Genomic and Computational Biology, Duke University School of Medicine, Durham, NC, 27710, USA. jentsan.chi@duke.edu.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines adaptatrices de la transduction du signal › RIPK3 upregulation confers robust...
questionsmedicales.fr › Eucaryotes › Animaux › RIPK3 upregulation confers robust...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Croissance › Processus de croissance cellulaire › Prolifération cellulaire › RIPK3 upregulation confers robust...
questionsmedicales.fr › Acides aminés, peptides et protéines › Acides aminés › Acides aminés soufrés › Cystéine › Cystine › RIPK3 upregulation confers robust...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Épigenèse génétique › RIPK3 upregulation confers robust...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Régulation de l'expression des gènes tumoraux › RIPK3 upregulation confers robust...
questionsmedicales.fr › Maladies de l'animal › Tumeurs mammaires de l'animal › RIPK3 upregulation confers robust...
questionsmedicales.fr › Phénomènes génétiques › Division du noyau cellulaire › Mitose › RIPK3 upregulation confers robust...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Processus néoplasiques › Récidive tumorale locale › RIPK3 upregulation confers robust...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pipérazines › RIPK3 upregulation confers robust...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Receptor-Interacting Protein Serine-Threonine Kinases › RIPK3 upregulation confers robust...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › RIPK3 upregulation confers robust...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Transcriptome › RIPK3 upregulation confers robust...
questionsmedicales.fr › Techniques d'investigation › Évaluation préclinique de médicament › Tests de criblage d'agents antitumoraux › Test clonogénique de cellules souches tumorales › RIPK3 upregulation confers robust...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Phosphoprotéines › Protéine p53 suppresseur de tumeur › RIPK3 upregulation confers robust...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Régulation positive › RIPK3 upregulation confers robust...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines adaptatrices de la transduction du signal › Protéines de signalisation YAP › RIPK3 upregulation confers robust...