Replication and ribosomal stress induced by targeting pyrimidine synthesis and cellular checkpoints suppress p53-deficient tumors.


:p53-mutated tumors often exhibit increased resistance to standard chemotherapy and enhanced metastatic potential. Here we demonstrate that inhibition of dihydroorotate dehydrogenase (DHODH), a key enzyme of the de novo pyrimidine synthesis pathway, effectively decreases proliferation of cancer cells via induction of replication and ribosomal stress in a p53- and checkpoint kinase 1 (Chk1)-dependent manner. Mechanistically, a block in replication and ribosomal biogenesis result in p53 activation paralleled by accumulation of replication forks that activate the ataxia telangiectasia and Rad3-related kinase/Chk1 pathway, both of which lead to cell cycle arrest. Since in the absence of functional p53 the cell cycle arrest fully depends on Chk1, combined DHODH/Chk1 inhibition in p53-dysfunctional cancer cells induces aberrant cell cycle re-entry and erroneous mitosis, resulting in massive cell death. Combined DHODH/Chk1 inhibition effectively suppresses p53-mutated tumors and their metastasis, and therefore presents a promising therapeutic strategy for p53-mutated cancers.


Cell Death Dis


Cell death & disease


Hubackova S,Davidova E,Boukalova S,Kovarova J,Bajzikova M,Coelho A,Terp MG,Ditzel HJ,Rohlena J,Neuzil J




Has Abstract


2020-02-07 00:00:00












  • MiR34 inhibition induces human heart progenitor proliferation.

    abstract::MiR34 involvement in myocardial injury repair and ageing has been well documented in mouse model. Our aim was to establish whether the inhibition of miR34 expression through locked nucleic acid (LNA) could be used as a pharmacological intervention to enhance human heart repair. Cardiac progenitor cells were obtained b...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Iannolo G,Sciuto MR,Raffa GM,Pilato M,Conaldi PG

    更新日期:2018-03-06 00:00:00

  • Targeting MKK3 as a novel anticancer strategy: molecular mechanisms and therapeutical implications.

    abstract::Mitogen-activated protein kinase kinase 3 (MAP2K3, MKK3) is a member of the dual specificity protein kinase group that belongs to the MAP kinase kinase family. This kinase is activated by mitogenic or stress-inducing stimuli and participates in the MAP kinase-mediated signaling cascade, leading to cell proliferation a...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Baldari S,Ubertini V,Garufi A,D'Orazi G,Bossi G

    更新日期:2015-01-29 00:00:00

  • Activation of the c-Jun NH2-terminal kinase pathway by coronavirus infectious bronchitis virus promotes apoptosis independently of c-Jun.

    abstract::Mitogen-activated protein kinases (MAPKs) are conserved protein kinases that regulate a variety of important cellular signaling pathways. Among them, c-Jun N-terminal kinases (JNK) are known to be activated by various environmental stresses including virus infections. Previously, activation of the JNK pathway has been...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Fung TS,Liu DX

    更新日期:2017-12-13 00:00:00

  • Inhibition of Casein kinase-2 induces p53-dependent cell cycle arrest and sensitizes glioblastoma cells to tumor necrosis factor (TNFα)-induced apoptosis through SIRT1 inhibition.

    abstract::Glioblastoma multiforme (GBM) are resistant to TNFα-induced apoptosis and blockade of TNFα-induced NF-κB activation sensitizes glioma cells to apoptosis. As Casein kinase-2 (CK2) induces aberrant NF-κB activation and as we observed elevated CK2 levels in GBM tumors, we investigated the potential of CK2 inhibitors (CK2...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Dixit D,Sharma V,Ghosh S,Mehta VS,Sen E

    更新日期:2012-02-09 00:00:00

  • Gefitinib targets ZAP-70-expressing chronic lymphocytic leukemia cells and inhibits B-cell receptor signaling.

    abstract::Chronic lymphocytic leukemia (CLL) can be divided into groups based on biomarkers of poor prognosis. The expression of the tyrosine kinase ZAP-70 (member of the Syk tyrosine kinase family) in CLL cells is associated with shorter overall survival in CLL patients. Currently, there is a lack of targeted therapies for pat...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Dielschneider RF,Xiao W,Yoon JY,Noh E,Banerji V,Li H,Marshall AJ,Johnston JB,Gibson SB

    更新日期:2014-10-02 00:00:00

  • Inhibition of AIM2 inflammasome-mediated pyroptosis by Andrographolide contributes to amelioration of radiation-induced lung inflammation and fibrosis.

    abstract::Radiation-induced lung injury (RILI) is one of the most common and fatal complications of thoracic radiotherapy, whereas no effective interventions are available. Andrographolide, an active component extracted from Andrographis paniculate, is prescribed as a treatment for upper respiratory tract infection. Here we rep...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Gao J,Peng S,Shan X,Deng G,Shen L,Sun J,Jiang C,Yang X,Chang Z,Sun X,Feng F,Kong L,Gu Y,Guo W,Xu Q,Sun Y

    更新日期:2019-12-20 00:00:00

  • Mitochondrial ferritin protects the murine myocardium from acute exhaustive exercise injury.

    abstract::Mitochondrial ferritin (FtMt) is a mitochondrially localized protein possessing ferroxidase activity and the ability to store iron. FtMt overexpression in cultured cells protects against oxidative damage by sequestering redox-active, intracellular iron. Here, we found that acute exhaustive exercise significantly incre...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Wu W,Chang S,Wu Q,Xu Z,Wang P,Li Y,Yu P,Gao G,Shi Z,Duan X,Chang YZ

    更新日期:2016-11-17 00:00:00

  • The PAX6-ZEB2 axis promotes metastasis and cisplatin resistance in non-small cell lung cancer through PI3K/AKT signaling.

    abstract::Paired-box 6 (PAX6) is an important transcription factor required for the function of human neuroectodermal epithelial tissues. Previous studies have suggested that it is also expressed in several types of tumors and has an oncogenic role. However, little is known about its role in non-small cell lung cancer (NSCLC). ...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Wu DM,Zhang T,Liu YB,Deng SH,Han R,Liu T,Li J,Xu Y

    更新日期:2019-04-25 00:00:00

  • Novel osmotin attenuates glutamate-induced synaptic dysfunction and neurodegeneration via the JNK/PI3K/Akt pathway in postnatal rat brain.

    abstract::The glutamate-induced excitotoxicity pathway has been reported in several neurodegenerative diseases. Molecules that inhibit the release of glutamate or cause the overactivation of glutamate receptors can minimize neuronal cell death in these diseases. Osmotin, a homolog of mammalian adiponectin, is a plant protein fr...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Shah SA,Lee HY,Bressan RA,Yun DJ,Kim MO

    更新日期:2014-01-30 00:00:00

  • Regulation of the proapoptotic functions of prostate apoptosis response-4 (Par-4) by casein kinase 2 in prostate cancer cells.

    abstract::The proapoptotic protein, prostate apoptosis response-4 (Par-4), acts as a tumor suppressor in prostate cancer cells. The serine/threonine kinase casein kinase 2 (CK2) has a well-reported role in prostate cancer resistance to apoptotic agents or anticancer drugs. However, the mechanistic understanding on how CK2 suppo...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: de Thonel A,Hazoumé A,Kochin V,Isoniemi K,Jego G,Fourmaux E,Hammann A,Mjahed H,Filhol O,Micheau O,Rocchi P,Mezger V,Eriksson JE,Rangnekar VM,Garrido C

    更新日期:2014-01-23 00:00:00

  • Tip30 controls differentiation of murine mammary luminal progenitor to estrogen receptor-positive luminal cell through regulating FoxA1 expression.

    abstract::Estrogen receptor-alpha positive (ER(+)) breast cancers comprise the majority of human breast cancers, but molecular mechanisms underlying this subtype of breast cancers remain poorly understood. Here, we show that ER(+) mammary luminal tumors arising in Tip30(-/-)MMTV-Neu mice exhibited increased enrichment of lumina...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Chen F,Li A,Gao S,Hollern D,Williams M,Liu F,VanSickle EA,Andrechek E,Zhang C,Yang C,Luo R,Xiao H

    更新日期:2014-05-22 00:00:00

  • Intraperitoneal injection of IFN-γ restores microglial autophagy, promotes amyloid-β clearance and improves cognition in APP/PS1 mice.

    abstract::Autophagy is a major self-degradative process that maintains cellular homeostasis and function in mammalian cells. Autophagic dysfunction occurs in the early pathogenesis of Alzheimer's disease (AD) and directly regulates amyloid-β (Aβ) metabolism. Although it has been proven that the cytokine IFN-γ enhances autophagy...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: He Z,Yang Y,Xing Z,Zuo Z,Wang R,Gu H,Qi F,Yao Z

    更新日期:2020-06-08 00:00:00

  • GSK-3β-induced Tau pathology drives hippocampal neuronal cell death in Huntington's disease: involvement of astrocyte-neuron interactions.

    abstract::Glycogen synthase kinase-3β (GSK-3β) has emerged as a critical factor in several pathways involved in hippocampal neuronal maintenance and function. In Huntington's disease (HD), there are early hippocampal deficits both in patients and transgenic mouse models, which prompted us to investigate whether disease-specific...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: L'Episcopo F,Drouin-Ouellet J,Tirolo C,Pulvirenti A,Giugno R,Testa N,Caniglia S,Serapide MF,Cisbani G,Barker RA,Cicchetti F,Marchetti B

    更新日期:2016-04-28 00:00:00

  • Calcineurin suppresses AMPK-dependent cytoprotective autophagy in cardiomyocytes under oxidative stress.

    abstract::Calcineurin signalling plays a critical role in the pathogenesis of many cardiovascular diseases. Calcineurin has been proven to affect a series of signalling pathways and to exert a proapoptotic effect in cardiomyocytes. However, whether it is able to regulate autophagy remains largely unknown. Here, we report that p...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: He H,Liu X,Lv L,Liang H,Leng B,Zhao D,Zhang Y,Du Z,Chen X,Li S,Lu Y,Shan H

    更新日期:2014-01-16 00:00:00

  • Metabolic reprogramming of acute lymphoblastic leukemia cells in response to glucocorticoid treatment.

    abstract::Glucocorticoids (GCs) are metabolic hormones with immunosuppressive effects that have proven effective drugs against childhood acute lymphoblastic leukemia (ALL). Yet, the role of metabolic reprogramming in GC-induced ALL cell death is poorly understood. GCs efficiently block glucose uptake and metabolism in ALL cells...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Dyczynski M,Vesterlund M,Björklund AC,Zachariadis V,Janssen J,Gallart-Ayala H,Daskalaki E,Wheelock CE,Lehtiö J,Grandér D,Tamm KP,Nilsson R

    更新日期:2018-08-28 00:00:00

  • Loss of apoptosis-inducing factor critically affects MIA40 function.

    abstract::Mitochondrial apoptosis-inducing factor (AIF) influences the oxidative phosphorylation (OXPHOS) system and can be recruited as a mediator of cell death. Pathogenic mutations in the AIFM1 gene cause severe human diseases. Clinical manifestations include inherited peripheral neuropathies, prenatal cerebral abnormalities...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Meyer K,Buettner S,Ghezzi D,Zeviani M,Bano D,Nicotera P

    更新日期:2015-07-09 00:00:00

  • Three-dimensional structure of Bax-mediated pores in membrane bilayers.

    abstract::B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax) is a member of the Bcl-2 protein family having a pivotal role in triggering cell commitment to apoptosis. Bax is latent and monomeric in the cytosol but transforms into its lethal, mitochondria-embedded oligomeric form in response to cell stress, leading to the rele...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Xu XP,Zhai D,Kim E,Swift M,Reed JC,Volkmann N,Hanein D

    更新日期:2013-06-20 00:00:00

  • Control of glioma cell death and differentiation by PKM2-Oct4 interaction.

    abstract::Glioma stem cells are highly resistant to cell death and as such are supposed to contribute to tumor recurrence by eluding anticancer treatments. Here, we show that spheroids that contain rat neural stem cells (NSCs) or rat glioma stem cells (cancer stem cells, CSCs) express isoforms 1 and 2 of pyruvate kinase (PKM1 a...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Morfouace M,Lalier L,Oliver L,Cheray M,Pecqueur C,Cartron PF,Vallette FM

    更新日期:2014-01-30 00:00:00

  • Superior antitumoral activity of dimerized targeted single-chain TRAIL fusion proteins under retention of tumor selectivity.

    abstract::Although targeting of the death receptors (DRs) DR4 and DR5 still appears a suitable antitumoral strategy, the limited clinical responses to recombinant soluble TNF-related apoptosis inducing ligand (TRAIL) necessitate novel reagents with improved apoptotic activity/tumor selectivity. Apoptosis induction by a single-c...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Siegemund M,Pollak N,Seifert O,Wahl K,Hanak K,Vogel A,Nussler AK,Göttsch D,Münkel S,Bantel H,Kontermann RE,Pfizenmaier K

    更新日期:2012-04-12 00:00:00

  • Long noncoding RNA lncARSR confers resistance to Adriamycin and promotes osteosarcoma progression.

    abstract::One of the significant challenges for chemotherapy is the appearance of resistance to compounds. Although several signaling pathways have been implicated in the development of Adriamycin (ADM) resistance, mechanisms involved in ADM-resistant osteosarcoma progression remain unknown. The present study attempted to illus...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Shen P,Cheng Y

    更新日期:2020-05-13 00:00:00

  • Correction: Salvador-Warts-Hippo pathway regulates sensory organ development via caspase-dependent nonapoptotic signaling.

    abstract::Following publication of this article, it was brought to our attention that there was a typo in the References (reference number 43) whereby the first author's name was misspelled. The correct citation is provided below. We apologize for the inconvenience. ...

    journal_title:Cell death & disease

    pub_type: 已发布勘误


    authors: Wang LH,Baker NE

    更新日期:2019-10-22 00:00:00

  • PI3K/mTOR pathway inhibitors sensitize chronic myeloid leukemia stem cells to nilotinib and restore the response of progenitors to nilotinib in the presence of stem cell factor.

    abstract::Nilotinib is a second-generation tyrosine kinase inhibitor, designed to specifically inhibit break-point cluster region (BCR)-Abelson (ABL) and developed to treat chronic myeloid leukemia (CML) in patients showing a resistance to imatinib. We previously demonstrated that nilotinib-induced apoptosis was reduced by stem...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Airiau K,Mahon FX,Josselin M,Jeanneteau M,Belloc F

    更新日期:2013-10-03 00:00:00

  • Comp34 displays potent preclinical antitumor efficacy in triple-negative breast cancer via inhibition of NUDT3-AS4, a novel oncogenic long noncoding RNA.

    abstract::The abnormal PI3K/AKT/mTOR pathway is one of the most common genomic abnormalities in breast cancers including triple-negative breast cancer (TNBC), and pharmacologic inhibition of these aberrations has shown activity in TNBC patients. Here, we designed and identified a small-molecule Comp34 that suppresses both AKT a...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Hao Q,Wang P,Dutta P,Chung S,Li Q,Wang K,Li J,Cao W,Deng W,Geng Q,Schrode K,Shaheen M,Wu K,Zhu D,Chen QH,Chen G,Elshimali Y,Vadgama J,Wu Y

    更新日期:2020-12-11 00:00:00

  • Loss of GCN5 leads to increased neuronal apoptosis by upregulating E2F1- and Egr-1-dependent BH3-only protein Bim.

    abstract::Cellular acetylation homeostasis is a kinetic balance precisely controlled by histone acetyl-transferase (HAT) and histone deacetylase (HDAC) activities. The loss of the counterbalancing function of basal HAT activity alters the precious HAT:HDAC balance towards enhanced histone deacetylation, resulting in a loss of a...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Wu Y,Ma S,Xia Y,Lu Y,Xiao S,Cao Y,Zhuang S,Tan X,Fu Q,Xie L,Li Z,Yuan Z

    更新日期:2017-01-26 00:00:00

  • Agonist antibodies activating the Met receptor protect cardiomyoblasts from cobalt chloride-induced apoptosis and autophagy.

    abstract::Met, the tyrosine kinase receptor for hepatocyte growth factor (HGF), mainly activates prosurvival pathways, including protection from apoptosis. In this work, we investigated the cardioprotective mechanisms of Met activation by agonist monoclonal antibodies (mAbs). Cobalt chloride (CoCl2), a chemical mimetic of hypox...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Gallo S,Gatti S,Sala V,Albano R,Costelli P,Casanova E,Comoglio PM,Crepaldi T

    更新日期:2014-04-17 00:00:00

  • Epigenetic silencing of ZNF132 mediated by methylation-sensitive Sp1 binding promotes cancer progression in esophageal squamous cell carcinoma.

    abstract::Epigenetic alteration of tumor suppression gene is one of the most significant indicators in human esophageal squamous cell carcinoma (ESCC). In this study, we identified a novel ESCC hypermethylation biomarker ZNF132 by integrative computational analysis to comprehensive genome-wide DNA methylation microarray dataset...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Jiang D,He Z,Wang C,Zhou Y,Li F,Pu W,Zhang X,Feng X,Zhang M,Yecheng X,Xu Y,Jin L,Guo S,Wang J,Wang M

    更新日期:2018-12-18 00:00:00

  • Caspase-1 is a novel target of p63 in tumor suppression.

    abstract::p63 is a p53 family transcription factor, which besides unique roles in epithelial development, shares tumor suppressive activity with its homolog p53. The p63 gene has different transcriptional start sites, which generate two N-terminal isoforms (transactivation domain (TA)p63 and amino terminal truncated protein(ΔN)...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Celardo I,Grespi F,Antonov A,Bernassola F,Garabadgiu AV,Melino G,Amelio I

    更新日期:2013-05-23 00:00:00

  • Deficiency in the autophagy modulator Dram1 exacerbates pyroptotic cell death of Mycobacteria-infected macrophages.

    abstract::DNA damage regulated autophagy modulator 1 (DRAM1) is a stress-inducible regulator of autophagy and cell death. DRAM1 has been implicated in cancer, myocardial infarction, and infectious diseases, but the molecular and cellular functions of this transmembrane protein remain poorly understood. Previously, we have propo...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Zhang R,Varela M,Forn-Cuní G,Torraca V,van der Vaart M,Meijer AH

    更新日期:2020-04-24 00:00:00

  • Parthenolide and DMAPT exert cytotoxic effects on breast cancer stem-like cells by inducing oxidative stress, mitochondrial dysfunction and necrosis.

    abstract::Triple-negative breast cancers (TNBCs) are aggressive forms of breast carcinoma associated with a high rate of recidivism. In this paper, we report the production of mammospheres from three lines of TNBC cells and demonstrate that both parthenolide (PN) and its soluble analog dimethylaminoparthenolide (DMAPT) suppress...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Carlisi D,Buttitta G,Di Fiore R,Scerri C,Drago-Ferrante R,Vento R,Tesoriere G

    更新日期:2016-04-14 00:00:00

  • Circular RNA FAM114A2 suppresses progression of bladder cancer via regulating ∆NP63 by sponging miR-762.

    abstract::Numerous evidences have shown that circular RNAs (circRNAs) play a key role in regulating the pathogenesis of cancer. However, the mechanism of circRNAs in urothelial carcinoma of bladder (UCB) remains largely unclear. In this study, we found circFAM114A2 was significantly downregulated both in UCB tissue specimens an...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Liu T,Lu Q,Liu J,Xie S,Feng B,Zhu W,Liu M,Liu Y,Zhou X,Sun W,Zhang Y,Chen X,Fang F,Guo H,Yang R

    更新日期:2020-01-22 00:00:00