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At least 1,495 records · Page 83
All sourcesNASA NTRSDOE OSTI
DOE OSTI2017

Lactate dehydrogenase-A is indispensable for vascular smooth muscle cell proliferation and migration

The proliferation and migration of vascular smooth muscle cells (VSMCs) have been implicated in the pathogenesis of atherosclerosis. Increased aerobic glycolysis is a key feature of cellular phenotypes including cancer and immune cells. However, the role of aerobic glycolysis in the atherogenic phenotype of VSMCs remains largely unknown. Here, we investigated the role of lactate dehydrogenase-A (LDHA), which is a key enzyme for glycolysis, in the proliferation and migration of VSMCs. Activation of primary rat VSMCs with fetal bovine serum (FBS) or platelet-derived growth factor (PDGF) increased their proliferation and migration, glycolytic activity, and expression of LDHA. Wound healing and transwell migration assays demonstrated that small interfering RNA-mediated knockdown of LDHA and pharmacological inhibition of LDHA by oxamate both effectively inhibited VSMC proliferation and migration. Inhibition of LDHA activity by oxamate reduced PDGF-stimulated glucose uptake, lactate production, and ATP production. Taken together, this study shows that enhanced glycolysis in PDGF- or FBS-stimulated VSMCs plays an important role in their proliferation and migration and suggests that LDHA is a potential therapeutic target to prevent vessel lumen constriction during the course of atherosclerosis and restenosis. - Highlights: • LDHA levels were upregulated in proliferative and migratory VSMCs. • Inhibition of LDHA suppressed growth factor-stimulated VSMC proliferation/migration. • Inhibition of LDHA reduced growth factor-stimulated glycolysis in VSMCs. • Targeting LDHA has a potential to treat excessive VSMC proliferation and migration.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Carbonyl cyanide 3-chlorophenylhydrazone (CCCP) suppresses STING-mediated DNA sensing pathway through inducing mitochondrial fission

Besides its important role in innate immune response to DNA virus infection, the regulatory function of STING in autoimmunity and cancer is emerging. Recently, multiple mechanisms regulating the activity of the STING pathway have been revealed. Previous study showed that carbonyl cyanide 3-chlorophenylhydrazone (CCCP), the protonophore, inhibited STING-mediated IFN-β production via disrupting mitochondrial membrane potential (MMP). However, how MMP dissipation leads to the suppression of the STING pathway remains unknown. Here, we show that CCCP inhibits activation of STING and its downstream signaling molecules, TBK1 and IRF3, but not STING translocation to the perinuclear region. We found that CCCP impairs the interaction between STING and TBK1 and concomitantly triggers mitochondria fission. Importantly, the knockout of the crucial mitochondria fission regulator Drp1 restored the STING activity, indicating that CCCP down-modulates the STING pathway through DRP1-mediated mitochondria fragmentation. Our findings highlight the coupling of the STING signaling platform to mitochondria dynamics. - Highlights: • CCCP inhibits IFN-β production induced by various types of the STING pathway activators. • CCCP suppresses the phosphorylation of STING, TBK1, and IRF3 via disrupting the association of STING and TBK1. • The mitochondria fission mediator DRP1 is essential for CCCP-induced suppression of the STING pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Caerulin-induced pro-inflammatory response in macrophages requires TRAF3-p38 signaling activation

Highlights: • Caerulin induces TRAF3 protein stabilization in mouse BMDMs. • Caerulin induces TRAF3 association with MKK3, mediating downstream p38 activation. • TRAF3 shRNA inhibits caerulin-induced pro-inflammatory cytokine production in BMDMs. • p38 blockage inhibits caerulin-induced pro-inflammatory cytokine production in BMDMs. • TRAF3 knockdown in caerulin-treated BMDMs alleviates cytotoxicity to pancreatic cells. Acute pancreatitis is a common threat to human health. Caerulin provokes severe inflammations, causing injuries to surrounding pancreatic cells. TNF receptor-associated factor 3 (TRAF3) is a highly versatile regulator of immune response. The current study aims to understand the potential effect of TRAF3 on caerulin-induced pro-inflammatory responses. In the primary-cultured mouse bone marrow–derived macrophages (BMDMs), caerulin induced TRAF3 protein stabilization, which formed a complex with mitogen-activated protein kinase kinase 3 (MKK3) to mediate downstream p38 activation. Lentiviral shRNA-mediated TRAF3 stable knockdown significantly attenuated caerulin-induced MKK3-p38 activation and production of several key pro-inflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and IL-17. Remarkably, TRAF3 knockdown in caerulin-stimulated BMDMs also alleviated cytotoxicity to Panc02 and primary mouse pancreatic cells. Thus, TRAF3 is required for caerulin-induced p38 activation and macrophage-mediated pro-inflammatory responses. TRAF3 expression in macrophages could be a novel therapeutic target protein for the treatment of acute pancreatitis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Sez6l2 regulates phosphorylation of ADD and neuritogenesis

Highlights: • Sez6l2 interacts with ADD and GluR1. • Extracellular domains of Sez6l2 and GluR1 are required for their interactions. • Sez6l2 may be one of the auxiliary subunits with AMPA receptors. • Sez6l2 may link GluR1 to ADD and be an up-regulator of ADD phosphorylation. Increasing evidence shows that immune-mediated mechanisms may contribute to the pathogenesis of central nervous system disorders including cerebellar ataxias, as indicated by the aberrant production of neuronal surface antibodies. We previously reported a patient with cerebellar ataxia associated with production of a new anti-neuronal antibody, anti-seizure-related 6 homolog like 2 (Sez6l2). Sez6l2 is a type 1 membrane protein that is highly expressed in the hippocampus and cerebellar cortex and mice lacking Sez6l2 protein family members develop ataxia. Here we used a proteomics-based approach to show that serum derived from this patient recognizes the extracellular domain of Sez6l2 and that Sez6l2 protein binds to both adducin (ADD) and glutamate receptor 1 (GluR1). Our results indicate that Sez6l2 is one of the auxiliary subunits of the AMPA receptor and acts as a scaffolding protein to link GluR1 to ADD. Furthermore, Sez6l2 overexpression upregulates ADD phosphorylation, whereas siRNA-mediated downregulation of Sez612 prevents ADD phosphorylation, suggesting that Sez6l2 modulates AMPA-ADD signal transduction.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

TβRIII is induced by TCR signaling and downregulated in FoxP3+ regulatory T cells

Highlights: • TβRIII is expressed in murine and human T lymphocytes but not on B cells. • TβRIII is preferentially expressed in naïve and central memory T cells, but it is very lowly expressed on regulatory T cells. • TβRIII is upregulated by TCR signaling, following similar kinetics to other early activation markers. • TβRIII is downregulated during iTreg induction in association with FoxP3 upregulation. TGF-β type III receptor (TβRIII) is a co-receptor for TGFβ family members required for high-affinity binding of these ligands to their receptors, potentiating their cellular functions. TGF-βs, Bone Morphogenetic Proteins (BMP2/4) and Inhibins/Activins regulate different checkpoints during T cell differentiation. We have previously reported that TβRIII modulates T cell development by protecting developing thymocytes from apoptosis, however the role of this co-receptor in peripheral lymphocytes still remains elusive. Here we describe a detailed characterization of TβRIII expression in murine and human lymphocyte subpopulations demonstrating that this co-receptor is significantly expressed in T but not B lymphocytes and among them, preferentially expressed on naïve and central memory T cells. TβRIII was upregulated after TCR stimulation, in parallel to other early activation markers. In contrast, natural and induced Tregs downregulated TβRIII in association with FoxP3 upregulation. Finally, anti-TβRIII blocking experiments demonstrated that TβRIII promotes TGFβ-dependent iTreg conversion in vitro, and suggest that this co-receptor may be involved in modulating peripheral T cell tolerance and could be considered as a potential target to boost T cell immune responses.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

MeWRKY20 and its interacting and activating autophagy-related protein 8 (MeATG8) regulate plant disease resistance in cassava

Highlights: • A systematic genome-wide of MeATGs is performed. • MeWRKY20 physically interacts with MeATG8a/8f/8h. • MeWRKY20 activates the transcription of MeATG8a. • MeATG8s and MeWRKY20 regulate defense response in cassava. As a highly conserved mechanism, autophagy is responsible for the transport of cytoplasmic constituents in the vacuoles or lysosomes. Moreover, autophagy is essential for plant development and various stress responses. In this study, 34 MeATGs were systematically identified in cassava, and their transcripts were commonly regulated by Xanthomonas axonopodis pv manihotis (Xam). Through transient expression in Nicotiana benthamiana, the subcellular locations of 4 MeATG8s were revealed. Notably, MeWRKY20 was identified as physical interacting protein of MeATG8a/8f/8h and upstream transcriptional activator of MeATG8a. Through virus-induced gene silencing (VIGS) in cassava, we found that MeATG8-silenced and MeWRKY20-silenced plants resulted in disease sensitive, with less callose depositions and lower autophagic activity. This study may facilitate our understanding of the upstream MeWRKY20 and underlying target as well as interacting proteins of MeATG8s in immune response. Taken together, MeWRKY20 and MeATG8a/8f/8h are essential for disease resistance against bacterial blight by forming various transcriptional modules and interacting complex in cassava.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Exposure to cigarette smoke disturbs adipokines secretion causing intercellular damage and insulin resistance in high fructose diet-induced metabolic disorder mice

Highlights: • Cigarette smoke and fructose excess intake induce disruption to mechanisms involved in ROS generation and ER stress. • Damage of cellular organelles induced by cigarette smoke and high fructose feeding affects inflammatory response and alters secretion of adipokines. • Cigarette smoking and fructose excess intake are associated with metabolic syndrome. A large amount of fructose intake along with smoking is associated with increased incidence of diseases linked to metabolic syndrome. More research is necessary to understand the complex mechanism that ultimately results in metabolic syndrome and the effect, if any, of high fructose dietary intake and smoking on individual health. In this study, we investigated changes in ER-Golgi network and disturbance to secretion of adipokines induced by cigarette smoking (CS) and excess fructose intake and their contribution to the disruption of metabolic homeostasis. We used high fructose-induced metabolic disorder mice model by feeding them with high fructose diet for 8 weeks. For CS exposure experiment, these mice were exposed to CS for 28 days according to OECD guideline 412. Our results clearly showed that the immune system was suppressed and ER stress was induced in mice with exposure to CS and fed with high fructose. Furthermore, their concentrations of adipokines including leptin and adiponectin were aberrant. Such alteration in secretion of adipokines could cause insulin resistance which may lead to the development of type 2 diabetes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

3-(Naphthalen-2-yl(propoxy)methyl)azetidine hydrochloride attenuates NLRP3 inflammasome-mediated signaling pathway in lipopolysaccharide-stimulated BV2 microglial cells

Highlights: • KHG26792 attenuated LPS-induced TNF-α, IL-1β, and IL-6 level in BV2 cells. • KHG26792 attenuated LPS-induced ROS and nitrotyrosine level. • KHG26792 attenuated LPS-induced damage in mitochondrial potential. • KHG26792 attenuated LPS-induced expression of NLRP3, activated caspase-1, and ASC. • KHG26792 attenuated LPS-induced ATP level through P2X7 receptor. The nucleotide-binding and oligomerization domain-like receptor containing a pyrin domain 3 (NLRP3) inflammasome is a multiprotein complex with a role in innate immune responses. NLRP3 inflammasome dysfunction is a common feature of chronic inflammatory diseases. Microglia activation is also associated with neuroinflammatory pathologies. We previously reported that 3-(naphthalen-2-yl(propoxy)methyl)azetidine hydrochloride (KHG26792) reduced hypoxia-induced toxicity by modulating inflammation. However, no studies have elucidated the precise mechanisms for the anti-inflammatory action of KHG26792, in particular via inflammasome mediation. This study investigated the effects of KHG26792 on the inflammasome-mediated signaling pathway in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. KHG26792 significantly attenuated several inflammatory responses including tumor necrosis factor-α, interleukin-1β, interleukin-6, reactive oxygen species, and mitochondrial potential in these cells. KHG26792 also suppressed LPS-induced increase NLRP3, activated caspase-1, and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) levels. Furthermore, KHG26792 successfully blocked LPS-activated adenosine triphosphate (ATP) level, likely through the purinergic receptor P2X ligand-gated ion channel 7 (P2X7) receptor. Our results suggest that the anti-inflammatory functions of KHG26792 may be, at least in part, due to regulation of the P2X7R/NLRP3-mediated signaling pathway during microglial activation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Effects of oral and subcutaneous administration of HSP60 on myeloid-derived suppressor cells and atherosclerosis in ApoE−/− mice

HSP60 has been proved to be closely related to atherosclerosis due to its antigenicity. To determine this antigenicity effect, the ApoE−/− mice were fed with western-type diet and HSP60 was administrated orally or subcutaneously (SC) for potential vaccine against atherosclerosis. Here, we observed the ApoE−/− mice with oral HSP60 administration group showed a significant reduction in plaque size at the aortic root; accompanied by increased MSDCs (CD11b{sup +}Gr1{sup +}) in peripheral blood and spleen which was mostly composed of M-MDSCs (CD11b{sup +}LY6G{sup −}LY6C{sup high}), and increased plasma IL-10 and splenic Foxp3, Arg1, iNOS mRNA as well as decreased plasma IFN-γ and splenic T-bet mRNA compared to control group. Surprisingly, ApoE−/− mice with subcutaneous HSP60 administration group showed contrary results and their MDSCs were mostly composed of G-MDSCs (CD11b{sup +}LY6G{sup +}LY6C{sup low}). As expected, both PBS-oral and PBS-SC groups showed no significant effects on both the immune response and atherosclerotic plaque formation. In contrast, subcutaneous administration of HSP60 causes the opposite response. Thus, we propose the proper method for administering HSP60 as a new immunologic agent for prevention and treatment of atherosclerosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Surfactant protein D attenuates nitric oxide-stimulated apoptosis in rat chondrocyte by suppressing p38 MAPK signaling

Innate immune molecule surfactant protein D (SP-D), a member of the C-type lectin protein family, plays an indispensable role in host defense and the regulation of inflammation in the lung and other tissues. Osteoarthritis (OA) is a degenerative disease of cartilage, with inflammation that causes pathologic changes and tissue damage. However, it is unknown whether there exist SP-D expression and its potential role in the pathogenesis of OA. In this study, we examined SP-D expression and explored its biological function in a sodium nitroprusside (SNP)-stimulated rat chondrocytes and surgically-induced rat OA model. We found SP-D expression in both human and rat articular chondrocytes, with higher level in normal chondrocytes compared to in OA chondrocytes. Furthermore, In vivo study demonstrated that recombinant human SP-D (rhSP-D) ameliorated cartilage degeneration in surgically-induced rat OA model. In vitro cell culture study showed that rhSP-D markedly inhibited the expression of caspase-3 as an apoptosis biomarker, and decreased phosphorylation of p38 mitogen-activated protein kinase (MAPK), which resulted in maintaining normal nuclear morphology and increasing mitochondrial membrane potential in SNP-stimulated rat chondrocytes. Collectively, these findings indicate that SP-D expresses in articular chondrocytes and suppresses SNP-stimulated chondrocyte apoptosis and ameliorates cartilage degeneration via suppressing p38 MAPK activity.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Unexpected role of the IMD pathway in Drosophila gut defense against Staphylococcus aureus

Highlights: • Drosocrystallin (Dcy) is involved in resistance against oral infection with S. aureus in adult Drosophila. • The presence of S. aureus does not trigger reactive oxygen species (ROS) production in the gut. • The IMD pathway is required for the clearance of ingested S. aureus. In this study, fruit fly of the genus Drosophila is utilized as a suitable model animal to investigate the molecular mechanisms of innate immunity. To combat orally transmitted pathogenic Gram-negative bacteria, the Drosophila gut is armed with the peritrophic matrix, which is a physical barrier composed of chitin and glycoproteins: the Duox system that produces reactive oxygen species (ROS), which in turn sterilize infected microbes, and the IMD pathway that regulates the expression of antimicrobial peptides (AMPs), which in turn control ROS-resistant pathogens. However, little is known about the defense mechanisms against Gram-positive bacteria in the fly gut. Here, we show that the peritrophic matrix protects Drosophila against Gram-positive bacteria S. aureus. We also define the few roles of ROS in response to the infection and show that the IMD pathway is required for the clearance of ingested microbes, possibly independently from AMP expression. These findings provide a new aspect of the gut defense system of Drosophila, and helps to elucidate the processes of gut-microbe symbiosis and pathogenesis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Direct regulation of IL-2 by curcumin

Highlights: • Curcumin identified as a direct binding partner of IL-2. • Binding between IL-2 and IL-2 receptor alpha is reduced by curcumin. • Curcumin counteracts the side effect of IL-2, vascular leak syndrome. Interleukin-2 (IL-2) is a crucial growth factor for both regulatory and effector T cells. Thus, IL-2 plays a critical role in the stimulation and suppression of immune responses. Recently, anti-IL-2 antibodies (Abs) have been shown to possess strong IL-2 modulatory activities by affecting the interaction between IL-2 and IL-2 receptors. In this study, we screened an herbal library to identify a compound that regulates IL-2, which resulted in the identification of curcumin as a direct binder and inhibitor of IL-2. Curcumin is a phytochemical with well-known anti-cancer properties. In this study, curcumin mimicked or altered the binding pattern of anti-IL-2 Abs against IL-2 and remarkably inhibited the interaction of recombinant IL-2 with the IL-2 receptor α, CD25. Interestingly, curcumin neutralized the biological activities of IL-2 both in vitro and in vivo. In this report, we elucidated the unsolved mechanism of the anti-cancer effect of curcumin by identifying IL-2 as a direct molecular target. Curcumin, as a small molecule IL-2 modulator, has the potential to be used to treat IL-2 related pathologic conditions.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

GBP3 promotes glioma cell proliferation via SQSTM1/p62-ERK1/2 axis

Highlights: • GBP3, an interferon-inducible large GTPase, is highly elevated in human glioma tumors. • GBP3 promotes glioma cell growth in vitro and in vivo through the SQSTM1/p62-ERK1/2 pathway. • GBP3 expression predicts poor outcome of glioma patients. Guanylate binding proteins (GBPs) are interferon-inducible large GTPases and play a crucial role in cell-autonomous immunity. However, the biology function of GBPs in cancer remains elusive. GBP3 is specifically expressed in adult brain. Here we show that GBP3 is highly elevated in human glioma tumors and glioma cell lines. Overexpression of GBP3 dramatically increased glioma cell proliferation whereas silencing GBP3 by RNA interference produced opposite effects. We further showed that GBP3 expression was able to induce sequestosome-1(SQSTM1, also named p62) expression and activate extracellular signal-regulated kinase (ERK1/2). The SQSTM1-ERK1/2 signaling cascade was essential for GBP3-promoted cell growth because depletion of SQSTM1 markedly reduced the phosphorylated ERK1/2 levels and GBP3-mediated cell growth, and inhibition of mitogen-activated protein kinase/ERK kinase abolished GBP3-induced glioma cell proliferation. Consistently, GBP3 overexpression significantly promoted glioma tumor growth in vivo and its expression was inversely correlated with the survival rate of glioma patients. Taken together, these results for the first time suggest that GBP3 contributes to the proliferation of glioma cells via regulating SQSTM1-ERK1/2 pathway, and GBP3 might represent as a new potential therapeutic target against glioma.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

FOXJ1 promotes bladder cancer cell growth and regulates Warburg effect

Forkhead Box J1 (FOXJ1) which belongs to Fox gene family, plays complex and crucial roles in processes of development, organogenesis, regulation of the immune system, as well as progression of several malignancies. However, how FOXJ1 functions in bladder cancer remains unclear. Here, we report that FOXJ1 is upregulated in most bladder cancer patients, and predicts poor clinical outcomes. FOXJ1 facilitates bladder cancer cell proliferation and colony formation. FOXJ1 knockdown suppresses bladder tumor growth in nude mice. Mechanistically, FOXJ1 enhances glycolysis by increasing glucose uptake, lactate production and extracellular acidification rate (ECAR), and decreasing ATP generation and oxygen consumption rate (OCR) in bladder cancer cells. Our findings provide clues regarding the role of FOXJ1 as a tumor inducer in bladder cancer and an enhancer in glycolysis. Targeting FOXJ1 could be a potential therapeutic strategy in bladder cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Adipose tissue complement factor B promotes adipocyte maturation

Highlights: • Complement factor B protein is abundantly expressed in inflamed adipose tissue. • Serum complement factor B level showed a correlation with the degree of obesity. • Complement factor B promotes adipocyte maturation and lipid droplet formation. It is well-known that the complement system plays an essential role in host immunity. Observational studies have indicated that complement system-related molecules such as complement factor B (CfB) and other components are correlated with obesity and/or insulin resistance parameters. In this study, we investigated the role of adipocyte-derived CfB in adipose tissue metabolism.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

The role of N-terminal segment and membrane association in MyD88-mediated signaling

Highlights: • 21 AA MYD88 deletion mutant fails to support MyD88-mediated signaling. • WT MyD88 and 21 AA NTD peptide bind to the phosphatidic acid (PA). • Anchoring of MyD88 to cell membrane and addition of PA augments cell signaling. MyD88 is a central signaling mediator of innate immunity, composed of the N-terminal death (DD) and C-terminal Toll/interleukin-1 receptor (TIR) domain linked by an intermediary (INT) domain. We showed that the N-terminal domain (NTD), composed of apparently unstructured 21 amino-acid residues, is involved in localization and clustering of MyD88 and is required for the efficient signaling, since the deletion mutant is unable to reconstitute MyD88-dependent signaling. Furthermore, we found that the NTD peptide interacts with phosphatidic acid, which potentiates MyD88-mediated signaling through TLRs. Propranolol and expression of lysophosphatidyl acid acyltransferase 1, which increase the level of phosphatidic acid augment cell activation via MyD88. Moreover, anchoring of MyD88 to the cell membrane augments signaling supporting the importance of membrane localization in MyD88-mediated signaling.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Tyrosine kinase Fyn regulates iNOS expression in LPS-stimulated astrocytes via modulation of ERK phosphorylation

Highlights: • Fyn regulates LPS-induced iNOS expression in the cortices. • Fyn modulates iNOS expression and nitrite levels in LPS-stimulated astrocytes. • Fyn regulates iNOS expression in LPS-stimulated astrocytes via ERK phosphorylation. The high concentrations of nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) in activated glial cells in response to neuroinflammatory stimuli have neurotoxic effects on the brain. At basal levels, iNOS expression is low, and proinflammatory stimuli induce iNOS expression in astrocytes, microglia, and oligodendrocytes. Fyn, a non-receptor tyrosine kinase, regulates iNOS expression in several types of immune cells. However, its role in stimulated astrocytes is less clear. In this study, we investigated the role of Fyn in the regulation of lipopolysaccharide (LPS)-induced iNOS expression in astrocytes from mice and rats. Intracerebroventricular LPS injections in cortical regions enhanced iNOS mRNA and protein levels, which were increased in Fyn-deficient mice. Accordingly, LPS-induced nitrite production was enhanced in primary astrocytes cultured from Fyn-deficient mice or rats. Similar results were observed in cultured astrocytes after the siRNA-induced knockdown of Fyn expression. Finally, we observed increased LPS-induced extracellular signal-regulated protein kinase (ERK) activation in Fyn-deficient astrocytes. These results suggested that Fyn has a regulatory role in iNOS expression in astrocytes during neuroinflammatory responses.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

GSDME mediates caspase-3-dependent pyroptosis in gastric cancer

Highlights: • Pyroptosis can be fired in gastric cancer. • GSDME switches chemotherapy induced apoptosis to pyroptosis in GSDME high expressed gastric cancer cells. • GSDME mediates cancer cell pyroptosis dependent on caspase-3 cleavage. Gastric cancer is a malignancy that starts from the cells in the stomach with relatively low overall survival rate. Chemotherapy following resection surgery has been recommended as a curative strategy for gastric cancer. However, the mechanism of the chemotherapy drugs on gastric cancer is not completely understood. Pyroptosis is a form of programmed cell death and plays critical role in immunity. The role of pyroptosis on cancer cells is less known. In this study, we treated SGC-7901 and MKN-45 with 5-FU and found that the cell viability was significantly decreased. The release of LDH and the percentage of PI and APC Annexin-V double positive cells after 5-FU treatment were elevated compared to control group. Moreover, there were large bubbles blowing from the membrane of 5-FU-treated cells and the cleavage of GSDME but not GSDMD, which were blocked by the silence or specific inhibitor of caspase-3. Additionally, GSDME knockout by CRISPR-Cas9 switched 5-FU induced pyroptosis into apoptosis in SGC-7901. In conclusion, our findings firstly revealed that GSDME switches chemotherapy drug-induced caspase-3 dependent apoptosis into pyroptosis in gastric cancer cells.

60 APPLIED LIFE SCIENCES↗