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 Disjournal_title
Cell death & diseaseauthors
Li L,Su N,Zhou T,Zheng D,Wang Z,Chen H,Yuan S,Li Wdoi
10.1038/s41419-017-0161-xsubject
Has Abstractpub_date
2018-02-02 00:00:00pages
143issue
2issn
2041-4889pii
10.1038/s41419-017-0161-xjournal_volume
9pub_type
杂志文章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
更新日期:2016-08-04 00:00:00
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
更新日期:2021-01-18 00:00:00
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
更新日期:2013-03-07 00:00:00
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
更新日期:2020-11-12 00:00:00
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
更新日期:2017-05-25 00:00:00
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
更新日期:2018-12-11 00:00:00
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
更新日期:2018-10-22 00:00:00
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
更新日期:2016-10-13 00:00:00
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
更新日期:2011-05-19 00:00:00
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
更新日期:2017-05-11 00:00:00
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
更新日期:2016-11-10 00:00:00
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
更新日期:2014-11-06 00:00:00
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
更新日期:2013-06-20 00:00:00
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
更新日期:2014-04-24 00:00:00
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
更新日期:2015-06-11 00:00:00
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
更新日期:2020-06-05 00:00:00
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
更新日期:2020-11-19 00:00:00
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
更新日期:2019-08-22 00:00:00
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
更新日期:2020-01-13 00:00:00
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
更新日期:2020-03-13 00:00:00
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
更新日期:2013-08-08 00:00:00
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
更新日期:2020-09-22 00:00:00
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
更新日期:2015-07-09 00:00:00
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
更新日期:2019-02-25 00:00:00
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
更新日期:2019-11-14 00:00:00
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
更新日期:2018-08-30 00:00:00
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
更新日期:2019-09-24 00:00:00
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
更新日期:2010-04-01 00:00:00
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
更新日期:2017-03-23 00:00:00
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
更新日期:2019-04-05 00:00:00