Synthetic lethal metabolic targeting of cellular senescence in cancer therapy.

Abstract:

:Activated oncogenes and anticancer chemotherapy induce cellular senescence, a terminal growth arrest of viable cells characterized by S-phase entry-blocking histone 3 lysine 9 trimethylation (H3K9me3). Although therapy-induced senescence (TIS) improves long-term outcomes, potentially harmful properties of senescent tumour cells make their quantitative elimination a therapeutic priority. Here we use the Eµ-myc transgenic mouse lymphoma model in which TIS depends on the H3K9 histone methyltransferase Suv39h1 to show the mechanism and therapeutic exploitation of senescence-related metabolic reprogramming in vitro and in vivo. After senescence-inducing chemotherapy, TIS-competent lymphomas but not TIS-incompetent Suv39h1(-) lymphomas show increased glucose utilization and much higher ATP production. We demonstrate that this is linked to massive proteotoxic stress, which is a consequence of the senescence-associated secretory phenotype (SASP) described previously. SASP-producing TIS cells exhibited endoplasmic reticulum stress, an unfolded protein response (UPR), and increased ubiquitination, thereby targeting toxic proteins for autophagy in an acutely energy-consuming fashion. Accordingly, TIS lymphomas, unlike senescence models that lack a strong SASP response, were more sensitive to blocking glucose utilization or autophagy, which led to their selective elimination through caspase-12- and caspase-3-mediated endoplasmic-reticulum-related apoptosis. Consequently, pharmacological targeting of these metabolic demands on TIS induction in vivo prompted tumour regression and improved treatment outcomes further. These findings unveil the hypercatabolic nature of TIS that is therapeutically exploitable by synthetic lethal metabolic targeting.

journal_name

Nature

journal_title

Nature

authors

Dörr JR,Yu Y,Milanovic M,Beuster G,Zasada C,Däbritz JH,Lisec J,Lenze D,Gerhardt A,Schleicher K,Kratzat S,Purfürst B,Walenta S,Mueller-Klieser W,Gräler M,Hummel M,Keller U,Buck AK,Dörken B,Willmitzer L,Reimann M,

doi

10.1038/nature12437

subject

Has Abstract

pub_date

2013-09-19 00:00:00

pages

421-5

issue

7467

eissn

0028-0836

issn

1476-4687

pii

nature12437

journal_volume

501

pub_type

杂志文章

相关文献

NATURE文献大全
  • Targeting of temperate phages drives loss of type I CRISPR-Cas systems.

    abstract::On infection of their host, temperate viruses that infect bacteria (bacteriophages; hereafter referred to as phages) enter either a lytic or a lysogenic cycle. The former results in lysis of bacterial cells and phage release (resulting in horizontal transmission), whereas lysogeny is characterized by the integration o...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/s41586-020-1936-2

    authors: Rollie C,Chevallereau A,Watson BNJ,Chyou TY,Fradet O,McLeod I,Fineran PC,Brown CM,Gandon S,Westra ER

    更新日期:2020-02-01 00:00:00

  • Genes encoding ligands for deletion of V beta 11 T cells cosegregate with mammary tumour virus genomes.

    abstract::The T-cell receptor (TCR) repertoire is selected in the thymus after rearrangement of genes encoding TCR alpha and beta chains. Selection is based on the recognition by newly emergent T cells of self-ligands associated with molecules of the major histocompatibility complex: some combinations result in positive selecti...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/349531a0

    authors: Dyson PJ,Knight AM,Fairchild S,Simpson E,Tomonari K

    更新日期:1991-02-07 00:00:00

  • RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia.

    abstract::Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs. Although chromatin alterations are, in princi...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature10334

    authors: Zuber J,Shi J,Wang E,Rappaport AR,Herrmann H,Sison EA,Magoon D,Qi J,Blatt K,Wunderlich M,Taylor MJ,Johns C,Chicas A,Mulloy JC,Kogan SC,Brown P,Valent P,Bradner JE,Lowe SW,Vakoc CR

    更新日期:2011-08-03 00:00:00

  • ATP-dependent inositide phosphorylation required for Ca(2+)-activated secretion.

    abstract::Regulated fusion of secretory granules with the plasma membrane in secretory cells requires ATP, Ca2+ and cytosolic as well as membrane proteins. ATP-dependent steps in Ca(2+)-activated secretion from PC12 cells require three cytosolic PEP proteins (priming in exocytosis proteins, PEP1-3), the identity of which will p...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/374173a0

    authors: Hay JC,Fisette PL,Jenkins GH,Fukami K,Takenawa T,Anderson RA,Martin TF

    更新日期:1995-03-09 00:00:00

  • The three-dimensional structure of foot-and-mouth disease virus at 2.9 A resolution.

    abstract::The structure of foot-and-mouth disease virus has been determined at close to atomic resolution by X-ray diffraction without experimental phase information. The virus shows similarities with other picornaviruses but also several unique features. The canyon or pit found in other picornaviruses is absent; this has impor...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/337709a0

    authors: Acharya R,Fry E,Stuart D,Fox G,Rowlands D,Brown F

    更新日期:1989-02-23 00:00:00

  • Ab initio alpha-alpha scattering.

    abstract::Processes such as the scattering of alpha particles ((4)He), the triple-alpha reaction, and alpha capture play a major role in stellar nucleosynthesis. In particular, alpha capture on carbon determines the ratio of carbon to oxygen during helium burning, and affects subsequent carbon, neon, oxygen, and silicon burning...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature16067

    authors: Elhatisari S,Lee D,Rupak G,Epelbaum E,Krebs H,Lähde TA,Luu T,Meißner UG

    更新日期:2015-12-03 00:00:00

  • Non-equivalent contributions of maternal and paternal genomes to early plant embryogenesis.

    abstract::Zygotic genome activation in metazoans typically occurs several hours to a day after fertilization, and thus maternal RNAs and proteins drive early animal embryo development. In plants, despite several molecular studies of post-fertilization transcriptional activation, the timing of zygotic genome activation remains a...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature13620

    authors: Del Toro-De León G,García-Aguilar M,Gillmor CS

    更新日期:2014-10-30 00:00:00

  • Assignment of the gene for human melanoma-associated antigen p97 to chromosome 3.

    abstract::p97 is a 97,000 molecular weight cell-surface glycoprotein, which is present in human melanomas but in only trace amounts in normal adult tissues. Amino acid sequence and iron binding studies have shown that p97 is structurally and functionally related to transferrin. Reports that the genes for the transferrin recepto...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/303070a0

    authors: Plowman GD,Brown JP,Enns CA,Schröder J,Nikinmaa B,Sussman HH,Hellström KE,Hellström I

    更新日期:1983-05-05 00:00:00

  • Author Correction: The selective tRNA aminoacylation mechanism based on a single G•U pair.

    abstract::In Fig. 1b of this Article, a U was inadvertently inserted after G15 in the D loop. The original Article has not been corrected. ...

    journal_title:Nature

    pub_type: 杂志文章,已发布勘误

    doi:10.1038/s41586-018-0760-4

    authors: Naganuma M,Sekine SI,Chong YE,Guo M,Yang XL,Gamper H,Hou YM,Schimmel P,Yokoyama S

    更新日期:2018-12-01 00:00:00

  • The perception of heading during eye movements.

    abstract::When a person walks through a rigid environment while holding eyes and head fixed, the pattern of retinal motion flows radially away from a point, the focus of expansion (Fig. 1a). Under such conditions of translation, heading corresponds to the focus of expansion and people identify it readily. But when making an eye...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/360583a0

    authors: Royden CS,Banks MS,Crowell JA

    更新日期:1992-12-10 00:00:00

  • The crown-of-thorns starfish genome as a guide for biocontrol of this coral reef pest.

    abstract::The crown-of-thorns starfish (COTS, the Acanthaster planci species group) is a highly fecund predator of reef-building corals throughout the Indo-Pacific region. COTS population outbreaks cause substantial loss of coral cover, diminishing the integrity and resilience of reef ecosystems. Here we sequenced genomes of CO...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature22033

    authors: Hall MR,Kocot KM,Baughman KW,Fernandez-Valverde SL,Gauthier MEA,Hatleberg WL,Krishnan A,McDougall C,Motti CA,Shoguchi E,Wang T,Xiang X,Zhao M,Bose U,Shinzato C,Hisata K,Fujie M,Kanda M,Cummins SF,Satoh N,Degnan SM

    更新日期:2017-04-05 00:00:00

  • Biotechnology regulation: rules for freed organisms planned.

    abstract::The Environmental Protection Agency is preparing to regulate the biotechnology industry, claiming authority under the provisions of the Federal Toxic Substances Control Act (TOSCA) and the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA). In the agency's view, the products of recombinant DNA techniques can...

    journal_title:Nature

    pub_type: 新闻

    doi:10.1038/306005a0

    authors: Earl C

    更新日期:1983-11-03 00:00:00

  • Taking dendritic cells into medicine.

    abstract::Dendritic cells (DCs) orchestrate a repertoire of immune responses that bring about resistance to infection and silencing or tolerance to self. In the settings of infection and cancer, microbes and tumours can exploit DCs to evade immunity, but DCs also can generate resistance, a capacity that is readily enhanced with...

    journal_title:Nature

    pub_type: 杂志文章,评审

    doi:10.1038/nature06175

    authors: Steinman RM,Banchereau J

    更新日期:2007-09-27 00:00:00

  • An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis.

    abstract::Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis, is a major cause of morbidity and mortality worldwide. Efforts to control it are hampered by difficulties with diagnosis, prevention and treatment. Most people infected with M. tuberculosis remain asymptomatic, termed latent TB, with a 10% lifetim...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature09247

    authors: Berry MP,Graham CM,McNab FW,Xu Z,Bloch SA,Oni T,Wilkinson KA,Banchereau R,Skinner J,Wilkinson RJ,Quinn C,Blankenship D,Dhawan R,Cush JJ,Mejias A,Ramilo O,Kon OM,Pascual V,Banchereau J,Chaussabel D,O'Garra A

    更新日期:2010-08-19 00:00:00

  • Biosynthesis of membrane factor B by mouse peritoneal macrophages.

    abstract::The biosynthesis of many of the complement proteins by cells of the monocyte-macrophage series has been established. Studies on these cells using radiolabelled amino acids demonstrated synthesis of precursor proteins (pro-complement), and the native complement protein similar in size to that found in the plasma. Howev...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/298389a0

    authors: Ooi YM,Ooi BS

    更新日期:1982-07-22 00:00:00

  • Redox-mediated substrate recognition by Sdp1 defines a new group of tyrosine phosphatases.

    abstract::Reactive oxygen species trigger cellular responses by activation of stress-responsive mitogen-activated protein kinase (MAPK) signalling pathways. Reversal of MAPK activation requires the transcriptional induction of specialized cysteine-based phosphatases that mediate MAPK dephosphorylation. Paradoxically, oxidative ...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature05804

    authors: Fox GC,Shafiq M,Briggs DC,Knowles PP,Collister M,Didmon MJ,Makrantoni V,Dickinson RJ,Hanrahan S,Totty N,Stark MJ,Keyse SM,McDonald NQ

    更新日期:2007-05-24 00:00:00

  • Universal structure of dark matter haloes over a mass range of 20 orders of magnitude.

    abstract::Cosmological models in which dark matter consists of cold elementary particles predict that the dark halo population should extend to masses many orders of magnitude below those at which galaxies can form1-3. Here we report a cosmological simulation of the formation of present-day haloes over the full range of observe...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/s41586-020-2642-9

    authors: Wang J,Bose S,Frenk CS,Gao L,Jenkins A,Springel V,White SDM

    更新日期:2020-09-01 00:00:00

  • Reduced nitrogen fixation in the glacial ocean inferred from changes in marine nitrogen and phosphorus inventories.

    abstract::To explain the lower atmospheric CO2 concentrations during glacial periods, it has been suggested that the productivity of marine phytoplankton was stimulated by an increased flux of iron-bearing dust to the oceans. One component of this theory is that iron-an essential element/nutrient for nitrogen-fixing organisms-w...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/415156a

    authors: Ganeshram RS,Pedersen TF,Calvert S,François R

    更新日期:2002-01-10 00:00:00

  • The genetic defect in familial Alzheimer's disease is not tightly linked to the amyloid beta-protein gene.

    abstract::Amyloid beta-protein (AP) is a peptide of relative molecular mass (Mr) 42,000 found in the senile plaques, cerebrovascular amyloid deposits, and neurofibrillary tangles of patients with Alzheimer's disease and Down's syndrome (trisomy 21). Recent molecular genetic evidence has indicated that AP is encoded as part of a...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/329156a0

    authors: Tanzi RE,St George-Hyslop PH,Haines JL,Polinsky RJ,Nee L,Foncin JF,Neve RL,McClatchey AI,Conneally PM,Gusella JF

    更新日期:1987-09-10 00:00:00

  • Evidence for a viral superantigen in humans.

    abstract::Superantigens bind class II major histocompatibility proteins and stimulate powerful proliferative responses of T lymphocytes bearing particular V beta sequences as part of their alpha beta antigen receptor. Exogenous bacterial superantigens are responsible for food poisoning and toxic shock syndrome. Murine virus-enc...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/358507a0

    authors: Lafon M,Lafage M,Martinez-Arends A,Ramirez R,Vuillier F,Charron D,Lotteau V,Scott-Algara D

    更新日期:1992-08-06 00:00:00

  • Detection and imaging of atmospheric radio flashes from cosmic ray air showers.

    abstract::The nature of ultrahigh-energy cosmic rays (UHECRs) at energies >10(20) eV remains a mystery. They are likely to be of extragalactic origin, but should be absorbed within approximately 50 Mpc through interactions with the cosmic microwave background. As there are no sufficiently powerful accelerators within this dista...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature03614

    authors: Falcke H,Apel WD,Badea AF,Bähren L,Bekk K,Bercuci A,Bertaina M,Biermann PL,Blümer J,Bozdog H,Brancus IM,Buitink S,Brüggemann M,Buchholz P,Butcher H,Chiavassa A,Daumiller K,de Bruyn AG,de Vos CM,Di Pierro F,Doll P

    更新日期:2005-05-19 00:00:00

  • An enzymatic Alder-ene reaction.

    abstract::An ongoing challenge in chemical research is to design catalysts that select the outcomes of the reactions of complex molecules. Chemists rely on organocatalysts or transition metal catalysts to control stereoselectivity, regioselectivity and periselectivity (selectivity among possible pericyclic reactions). Nature ac...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/s41586-020-2743-5

    authors: Ohashi M,Jamieson CS,Cai Y,Tan D,Kanayama D,Tang MC,Anthony SM,Chari JV,Barber JS,Picazo E,Kakule TB,Cao S,Garg NK,Zhou J,Houk KN,Tang Y

    更新日期:2020-10-01 00:00:00

  • Coupled dynamics of body mass and population growth in response to environmental change.

    abstract::Environmental change has altered the phenology, morphological traits and population dynamics of many species. However, the links underlying these joint responses remain largely unknown owing to a paucity of long-term data and the lack of an appropriate analytical framework. Here we investigate the link between phenoty...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature09210

    authors: Ozgul A,Childs DZ,Oli MK,Armitage KB,Blumstein DT,Olson LE,Tuljapurkar S,Coulson T

    更新日期:2010-07-22 00:00:00

  • Feedback regulation of steady-state epithelial turnover and organ size.

    abstract::Epithelial organs undergo steady-state turnover throughout adult life, with old cells being continually replaced by the progeny of stem cell divisions. To avoid hyperplasia or atrophy, organ turnover demands strict equilibration of cell production and loss. However, the mechanistic basis of this equilibrium is unknown...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature23678

    authors: Liang J,Balachandra S,Ngo S,O'Brien LE

    更新日期:2017-08-31 00:00:00

  • MHC-II neoantigens shape tumour immunity and response to immunotherapy.

    abstract::The ability of the immune system to eliminate and shape the immunogenicity of tumours defines the process of cancer immunoediting1. Immunotherapies such as those that target immune checkpoint molecules can be used to augment immune-mediated elimination of tumours and have resulted in durable responses in patients with...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/s41586-019-1671-8

    authors: Alspach E,Lussier DM,Miceli AP,Kizhvatov I,DuPage M,Luoma AM,Meng W,Lichti CF,Esaulova E,Vomund AN,Runci D,Ward JP,Gubin MM,Medrano RFV,Arthur CD,White JM,Sheehan KCF,Chen A,Wucherpfennig KW,Jacks T,Unanue ER,Ar

    更新日期:2019-10-01 00:00:00

  • Genome organization and transactivation of the human immunodeficiency virus type 2.

    abstract::Analysis of the nucleotide sequence of the human retrovirus associated with AIDS in West Africa, HIV-2, shows that it is evolutionarily distant from the previously characterized HIV-1. We suggest that these viruses existed long before the current AIDS epidemics. Their biological properties are conserved in spite of li...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/326662a0

    authors: Guyader M,Emerman M,Sonigo P,Clavel F,Montagnier L,Alizon M

    更新日期:1987-04-16 00:00:00

  • The dynamics of molecular evolution over 60,000 generations.

    abstract::The outcomes of evolution are determined by a stochastic dynamical process that governs how mutations arise and spread through a population. However, it is difficult to observe these dynamics directly over long periods and across entire genomes. Here we analyse the dynamics of molecular evolution in twelve experimenta...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature24287

    authors: Good BH,McDonald MJ,Barrick JE,Lenski RE,Desai MM

    更新日期:2017-11-02 00:00:00

  • Substantial reservoirs of molecular hydrogen in the debris disks around young stars.

    abstract::Circumstellar accretion disks transfer matter from molecular clouds to young stars and to the sites of planet formation. The disks observed around pre-main-sequence stars have properties consistent with those expected for the pre-solar nebula from which our own Solar System formed 4.5 Gyr ago. But the 'debris' disks t...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/35051033

    authors: Thi WF,Blake GA,van Dishoeck EF,van Zadelhoff GJ,Horn JM,Becklin EE,Mannings V,Sargent AI,van Den Ancker ME,Natta A

    更新日期:2001-01-04 00:00:00

  • Are U4 small nuclear ribonucleoproteins involved in polyadenylation?

    abstract::The mechanism whereby eukaryotic pre-messenger RNAs are polyadenylated is unknown. Most models for polyadenylation invoke cleavage of precursor transcripts at the site of poly(A) addition followed by polymerization of A residues by poly(A) polymerase. Analysis of the sequences surrounding poly(A) addition sites has id...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/309179a0

    authors: Berget SM

    更新日期:1984-05-10 00:00:00

  • Multigate transistors as the future of classical metal-oxide-semiconductor field-effect transistors.

    abstract::For more than four decades, transistors have been shrinking exponentially in size, and therefore the number of transistors in a single microelectronic chip has been increasing exponentially. Such an increase in packing density was made possible by continually shrinking the metal-oxide-semiconductor field-effect transi...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature10676

    authors: Ferain I,Colinge CA,Colinge JP

    更新日期:2011-11-16 00:00:00