Mixed lineage kinase ZAK promotes epithelial-mesenchymal transition in cancer progression.

Abstract:

:ZAK, a mixed lineage kinase, is often described as a positive or negative regulator of cell growth. We identified it as one of the top hits in our kinome cDNA screen for potent regulators of epithelial mesenchymal transition (EMT). Ectopic expression of ZAK promoted EMT phenotypes and apoptosis resistance in multiple epithelial cell lines, while having different impacts on cell growth in different cell lines. Conversely, depletion of ZAK in aggressive mesenchymal cancer cells reversed EMT phenotypes, increased sensitivity to conventional cytotoxic drugs, and attenuated bone metastasis potential, with little impact on primary tumor growth. Mechanistically, ZAK-mediated EMT is associated with activation of ZEB1 and suppression of epithelial splicing regulatory proteins (ESRPs), which results in a switch in CD44 expression from the epithelial CD44v8-9 isoform to the mesenchymal CD44s isoform. Of note, transcriptomic analysis showed that ZAK overexpression is significantly associated with poor survival in a number of human cancer types. Tissue microarray analysis on breast invasive carcinoma further supported that ZAK overexpression is an independent poor prognostic factor for overall survival in breast cancer. Through combination with ZAK, prognostic accuracy of other common clinicopathological markers in breast cancer is improved by up to 21%. Taken together, these results suggest that promoting EMT is the primary role for ZAK in cancer progression. They also highlight its potential as a biomarker to identify high-risk patients, and suggest its promise as a therapeutic target for inhibiting metastasis and overcoming drug resistance.

journal_name

Cell Death Dis

journal_title

Cell death & disease

authors

Li L,Su N,Zhou T,Zheng D,Wang Z,Chen H,Yuan S,Li W

doi

10.1038/s41419-017-0161-x

subject

Has Abstract

pub_date

2018-02-02 00:00:00

pages

143

issue

2

issn

2041-4889

pii

10.1038/s41419-017-0161-x

journal_volume

9

pub_type

杂志文章
  • Inhibitor of apoptosis protein expression in glioblastomas and their in vitro and in vivo targeting by SMAC mimetic GDC-0152.

    abstract::Glioblastomas (GBMs) are the most aggressive primary brain tumors in adult and remain a therapeutic challenge. Targeting key apoptosis regulators with the ultimate aim to restore apoptosis in tumor cells could be an interesting therapeutic strategy. The inhibitors of apoptosis proteins (IAPs) are regulators of cell de...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/cddis.2016.214

    authors: Tchoghandjian A,Soubéran A,Tabouret E,Colin C,Denicolaï E,Jiguet-Jiglaire C,El-Battari A,Villard C,Baeza-Kallee N,Figarella-Branger D

    更新日期:2016-08-04 00:00:00

  • Survival control of oligodendrocyte progenitor cells requires the transcription factor 4 during olfactory bulb development.

    abstract::A proper number of oligodendrocytes in the nerve system is essential for neuronal functions. In the olfactory bulb (OB), enriched oligodendrocytes are crucial for olfactory information processing. However, how the precise number of oligodendrocytes in the OB is regulated remains elusive. Here we identified that the tr...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/s41419-020-03371-3

    authors: Zhang Y,Cai Y,Wang Y,Deng X,Zhao Y,Zhang Y,Xie Y

    更新日期:2021-01-18 00:00:00

  • Neurogenin 3+ cells contribute to β-cell neogenesis and proliferation in injured adult mouse pancreas.

    abstract::We previously showed that injury by partial duct ligation (PDL) in adult mouse pancreas activates Neurogenin 3 (Ngn3)(+) progenitor cells that can differentiate to β cells ex vivo. Here we evaluate the role of Ngn3(+) cells in β cell expansion in situ. PDL not only induced doubling of the β cell volume but also increa...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/cddis.2013.52

    authors: Van de Casteele M,Leuckx G,Baeyens L,Cai Y,Yuchi Y,Coppens V,De Groef S,Eriksson M,Svensson C,Ahlgren U,Ahnfelt-Rønne J,Madsen OD,Waisman A,Dor Y,Jensen JN,Heimberg H

    更新日期:2013-03-07 00:00:00

  • DEPTOR is a direct p53 target that suppresses cell growth and chemosensitivity.

    abstract::DEP-domain containing mTOR-interacting protein (DEPTOR), a natural mTOR inhibitor, has essential roles in several processes, including cell growth, metabolism, apoptosis, and immunity. DEPTOR expression has been shown to be diversely controlled at transcriptional levels in cell- and context-specific manners. However, ...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/s41419-020-03185-3

    authors: Cui D,Dai X,Gong L,Chen X,Wang L,Xiong X,Zhao Y

    更新日期:2020-11-12 00:00:00

  • miR-21 ablation and obeticholic acid ameliorate nonalcoholic steatohepatitis in mice.

    abstract::This corrects the article DOI: 10.1038/cddis.2017.172. ...

    journal_title:Cell death & disease

    pub_type: 杂志文章,已发布勘误

    doi:10.1038/cddis.2017.246

    authors: Rodrigues PM,Afonso MB,Simão AL,Carvalho CC,Trindade A,Duarte A,Borralho PM,Machado MV,Cortez-Pinto H,Rodrigues CM,Castro RE

    更新日期:2017-05-25 00:00:00

  • GPx1 is involved in the induction of protective autophagy in pancreatic cancer cells in response to glucose deprivation.

    abstract::Given the dense stroma and poor vascularization, access to nutrients is limited in the microenvironment of pancreatic ductal adenocarcinoma (PDA). PDA cells can efficiently recycle various metabolic substrates through the activation of different rescuing pathways, including the autophagy pathway. However, the precise ...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/s41419-018-1244-z

    authors: Meng Q,Xu J,Liang C,Liu J,Hua J,Zhang Y,Ni Q,Shi S,Yu X

    更新日期:2018-12-11 00:00:00

  • Azithromycin promotes alternatively activated macrophage phenotype in systematic lupus erythematosus via PI3K/Akt signaling pathway.

    abstract::Alternatively activated macrophages have been reported to be helpful to alleviate systematic lupus erythematosus (SLE), and azithromycin could serve as an immunomodulator by promoting alternatively activated macrophage phenotype. However, the effect of azithromycin in SLE and the involved mechanism remain undetermined...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/s41419-018-1097-5

    authors: Wang J,Xie L,Wang S,Lin J,Liang J,Xu J

    更新日期:2018-10-22 00:00:00

  • DDX3 DEAD-box RNA helicase plays a central role in mitochondrial protein quality control in Leishmania.

    abstract::DDX3 is a highly conserved member of ATP-dependent DEAD-box RNA helicases with multiple functions in RNA metabolism and cellular signaling. Here, we describe a novel function for DDX3 in regulating the mitochondrial stress response in the parasitic protozoan Leishmania. We show that genetic inactivation of DDX3 leads ...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/cddis.2016.315

    authors: Padmanabhan PK,Zghidi-Abouzid O,Samant M,Dumas C,Aguiar BG,Estaquier J,Papadopoulou B

    更新日期:2016-10-13 00:00:00

  • Involvement of lipid rafts in the localization and dysfunction effect of the antitumor ether phospholipid edelfosine in mitochondria.

    abstract::Lipid rafts and mitochondria are promising targets in cancer therapy. The synthetic antitumor alkyl-lysophospholipid analog edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) has been reported to target lipid rafts. Here, we have found that edelfosine induced loss of mitochondrial membrane potential an...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/cddis.2011.41

    authors: Mollinedo F,Fernández M,Hornillos V,Delgado J,Amat-Guerri F,Acuña AU,Nieto-Miguel T,Villa-Pulgarín JA,González-García C,Ceña V,Gajate C

    更新日期:2011-05-19 00:00:00

  • TXNIP regulates mitophagy in retinal Müller cells under high-glucose conditions: implications for diabetic retinopathy.

    abstract::Thioredoxin-interacting protein (TXNIP) is involved in oxidative stress and apoptosis in diabetic retinopathy. However, the role of TXNIP in the removal of damaged mitochondria (MT) via mitophagy, a process of macroautophagy, remains unexplored. Here we investigate the associated cellular and molecular mechanisms unde...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/cddis.2017.190

    authors: Devi TS,Somayajulu M,Kowluru RA,Singh LP

    更新日期:2017-05-11 00:00:00

  • Manipulating the air-filled zebrafish swim bladder as a neutrophilic inflammation model for acute lung injury.

    abstract::Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), are life-threatening diseases that are associated with high mortality rates due to treatment limitations. Neutrophils play key roles in the pathogenesis of ALI/ARDS by promoting the inflammation and injury of the alveolar mic...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/cddis.2016.365

    authors: Zhang Y,Liu H,Yao J,Huang Y,Qin S,Sun Z,Xu Y,Wan S,Cheng H,Li C,Zhang X,Ke Y

    更新日期:2016-11-10 00:00:00

  • PGC-1α buffers ROS-mediated removal of mitochondria during myogenesis.

    abstract::Mitochondrial biogenesis and mitophagy are recognized as critical processes underlying mitochondrial homeostasis. However, the molecular pathway(s) coordinating the balance between these cellular programs is still poorly investigated. Here, we show an induction of the nuclear and mitochondrial peroxisome proliferator-...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/cddis.2014.458

    authors: Baldelli S,Aquilano K,Ciriolo MR

    更新日期:2014-11-06 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

    doi:10.1038/cddis.2013.210

    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

  • Identification of ML-9 as a lysosomotropic agent targeting autophagy and cell death.

    abstract::The growing number of studies suggested that inhibition of autophagy enhances the efficacy of Akt kinase inhibitors in cancer therapy. Here, we provide evidence that ML-9, a widely used inhibitor of Akt kinase, myosin light-chain kinase (MLCK) and stromal interaction molecule 1 (STIM1), represents the 'two-in-one' com...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/cddis.2014.156

    authors: Kondratskyi A,Yassine M,Slomianny C,Kondratska K,Gordienko D,Dewailly E,Lehen'kyi V,Skryma R,Prevarskaya N

    更新日期:2014-04-24 00:00:00

  • Early downregulation of Mcl-1 regulates apoptosis triggered by cardiac glycoside UNBS1450.

    abstract::Cardiac glycosides (CGs), prescribed to treat cardiovascular alterations, display potent anti-cancer activities. Despite their well-established target, the sodium/potassium (Na(+)/K(+))-ATPase, downstream mechanisms remain poorly elucidated. UNBS1450 is a hemi-synthetic cardenolide derived from 2″-oxovorusharin extrac...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/cddis.2015.134

    authors: Cerella C,Muller F,Gaigneaux A,Radogna F,Viry E,Chateauvieux S,Dicato M,Diederich M

    更新日期:2015-06-11 00:00:00

  • FOXF2 acts as a crucial molecule in tumours and embryonic development.

    abstract::As a key member of the forkhead box transcription factors, forkhead box F2 (FOXF2) serves as a transcriptional regulator and regulates downstream gene expression in embryonic development, metabolism and in some common diseases, such as stroke and gastroparesis. Recent studies have shown that aberrant expression of FOX...

    journal_title:Cell death & disease

    pub_type: 杂志文章,评审

    doi:10.1038/s41419-020-2604-z

    authors: He W,Kang Y,Zhu W,Zhou B,Jiang X,Ren C,Guo W

    更新日期:2020-06-05 00:00:00

  • Tumor necrosis factor α inhibition overcomes immunosuppressive M2b macrophage-induced bevacizumab resistance in triple-negative breast cancer.

    abstract::Bevacizumab in neoadjuvant therapy provides a new hope of improved survival for patients with triple-negative breast cancer (TNBC) by targeting vascular endothelial growth factor in combination with chemotherapy, but curative effect is limited by bevacizumab's continuous use while mechanisms remain incompletely unders...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/s41419-020-03161-x

    authors: Liu Y,Ji X,Kang N,Zhou J,Liang X,Li J,Han T,Zhao C,Yang T

    更新日期:2020-11-19 00:00:00

  • Retraction Note: HDAC6 inhibitor TST strengthens the antiproliferative effects of PI3K/mTOR inhibitor BEZ235 in breast cancer cells via suppressing RTK activation.

    abstract::An amendment to this paper has been published and can be accessed via a link at the top of the paper. ...

    journal_title:Cell death & disease

    pub_type: 杂志文章,撤回出版物

    doi:10.1038/s41419-019-1866-9

    authors: Sun S,Zhang Y,Zheng J,Duan B,Cui J,Chen Y,Deng W,Ye B,Liu L,Chen Y,Du J,Gu L

    更新日期:2019-08-22 00:00:00

  • Inhibition of thyroid hormone signaling protects retinal pigment epithelium and photoreceptors from cell death in a mouse model of age-related macular degeneration.

    abstract::Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. Dry AMD is characterized by a progressive macular degeneration of the retinal pigment epithelium (RPE) and photoreceptors, and the RPE oxidative damage/dystrophy is at the core of the disease. Recent population/patients-based stud...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/s41419-019-2216-7

    authors: Ma H,Yang F,Ding XQ

    更新日期:2020-01-13 00:00:00

  • MMP9 mediates acute hyperglycemia-induced human cardiac stem cell death by upregulating apoptosis and pyroptosis in vitro.

    abstract::Providing a conducive microenvironment is critical to increase survival of transplanted stem cells in regenerative therapy. Hyperglycemia promotes stem cell death impairing cardiac regeneration in the diabetic heart. Understanding the molecular mechanisms of high glucose-induced stem cell death is important for improv...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/s41419-020-2367-6

    authors: Yadav SK,Kambis TN,Kar S,Park SY,Mishra PK

    更新日期:2020-03-13 00:00:00

  • Marchantin M: a novel inhibitor of proteasome induces autophagic cell death in prostate cancer cells.

    abstract::We previously reported that marchantin M (Mar) is an active agent to induce apoptosis in human prostate cancer (PCa), but the molecular mechanisms of action remain largely unknown. Here, we demonstrate that Mar potently inhibited chymotrypsin-like and peptidyl-glutamyl peptide-hydrolyzing activities of 20S proteasome ...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/cddis.2013.285

    authors: Jiang H,Sun J,Xu Q,Liu Y,Wei J,Young CY,Yuan H,Lou H

    更新日期:2013-08-08 00:00:00

  • miR-196b-5p-mediated downregulation of FAS promotes NSCLC progression by activating IL6-STAT3 signaling.

    abstract::Our recent study demonstrated that the QKI-5 regulated miRNA, miR-196b-5p, and it functions as an onco-microRNA in non-small cell lung cancer (NSCLC) by directly targeting GATA6 and TSPAN12. However, the role of miR-196b-5p in NSCLC progression and metastasis still remains unclear. We found that miR-196b-5p promotes l...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/s41419-020-02997-7

    authors: Huang X,Xiao S,Zhu X,Yu Y,Cao M,Zhang X,Li S,Zhu W,Wu F,Zheng X,Jin L,Xie C,Huang X,Zou P,Li X,Cui R

    更新日期:2020-09-22 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

    doi:10.1038/cddis.2015.170

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

    更新日期:2015-07-09 00:00:00

  • Glycine decarboxylase induces autophagy and is downregulated by miRNA-30d-5p in hepatocellular carcinoma.

    abstract::Glycine decarboxylase (GLDC) belongs to the glycine cleavage system and is involved in one-carbon metabolism. We previously reported that GLDC downregulation enhances hepatocellular carcinoma (HCC) progression and intrahepatic metastasis through decreasing ROS-mediated ubiquitination of cofilin. The role of autophagy ...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/s41419-019-1446-z

    authors: Zhuang H,Wu F,Wei W,Dang Y,Yang B,Ma X,Han F,Li Y

    更新日期:2019-02-25 00:00:00

  • Autoantibodies to synapsin I sequestrate synapsin I and alter synaptic function.

    abstract::Synapsin I is a phosphoprotein that coats the cytoplasmic side of synaptic vesicles and regulates their trafficking within nerve terminals. Autoantibodies against Syn I have been described in sera and cerebrospinal fluids of patients with numerous neurological diseases, including limbic encephalitis and clinically iso...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/s41419-019-2106-z

    authors: Rocchi A,Sacchetti S,De Fusco A,Giovedi S,Parisi B,Cesca F,Höltje M,Ruprecht K,Ahnert-Hilger G,Benfenati F

    更新日期:2019-11-14 00:00:00

  • High NRF2 level mediates cancer stem cell-like properties of aldehyde dehydrogenase (ALDH)-high ovarian cancer cells: inhibitory role of all-trans retinoic acid in ALDH/NRF2 signaling.

    abstract::Aldehyde dehydrogenase 1A1 (ALDH1A1) is one of cancer stem cell (CSC) markers, and high ALDH1 expression has been related to drug resistance and facilitated tumor growth. In this study, we investigated the potential involvement of nuclear factor erythroid 2-like 2 (NFE2L2/NRF2) in CSC-like properties of ALDH-high ovar...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/s41419-018-0903-4

    authors: Kim D,Choi BH,Ryoo IG,Kwak MK

    更新日期:2018-08-30 00:00:00

  • Cystathionine β-synthase (CBS) deficiency suppresses erythropoiesis by disrupting expression of heme biosynthetic enzymes and transporter.

    abstract::The reduced iron usage induced by the suppression of erythropoiesis is a major cause of the systemic iron overload in CBS knockout (CBS-/-) mice. However, the relevant mechanisms are unknown. Here, we examined changes in granulocyte/erythroid cell ratios, iron content, and expression of iron-metabolism proteins, inclu...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/s41419-019-1951-0

    authors: Zhao P,Qian C,Chen YJ,Sheng Y,Ke Y,Qian ZM

    更新日期:2019-09-24 00:00:00

  • CXCL12 inhibits expression of the NMDA receptor's NR2B subunit through a histone deacetylase-dependent pathway contributing to neuronal survival.

    abstract::Homeostatic chemokines, such as CXCL12, can affect neuronal activity by the regulation of inhibitory and excitatory neurotransmission, but the mechanisms involved are still undefined. Our previous studies have shown that CXCL12 protects cortical neurons from excitotoxicity by promoting the function of the gene-repress...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/cddis.2010.10

    authors: Nicolai J,Burbassi S,Rubin J,Meucci O

    更新日期:2010-04-01 00:00:00

  • Metabolic and molecular insights into an essential role of nicotinamide phosphoribosyltransferase.

    abstract::Nicotinamide phosphoribosyltransferase (NAMPT) is a pleiotropic protein implicated in the pathogenesis of acute respiratory distress syndrome, aging, cancer, coronary heart diseases, diabetes, nonalcoholic fatty liver disease, obesity, rheumatoid arthritis, and sepsis. However, the underlying molecular mechanisms of N...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/cddis.2017.132

    authors: Zhang LQ,Van Haandel L,Xiong M,Huang P,Heruth DP,Bi C,Gaedigk R,Jiang X,Li DY,Wyckoff G,Grigoryev DN,Gao L,Li L,Wu M,Leeder JS,Ye SQ

    更新日期:2017-03-23 00:00:00

  • Imbalance of the spindle-assembly checkpoint promotes spindle poison-mediated cytotoxicity with distinct kinetics.

    abstract::Disrupting microtubule dynamics with spindle poisons activates the spindle-assembly checkpoint (SAC) and induces mitotic cell death. However, mitotic exit can occur prematurely without proper chromosomal segregation or cytokinesis by a process termed mitotic slippage. It remains controversial whether mitotic slippage ...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/s41419-019-1539-8

    authors: Zeng X,Xu WK,Lok TM,Ma HT,Poon RYC

    更新日期:2019-04-05 00:00:00