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Article ; Online: Vemurafenib activates the sonic hedgehog pathway and promotes thyroid cancer stem cell self-renewal.

Lu, Yurong / Zhao, Yuqing / Liu, Penggang / Xu, Xiulong

2023 Volume 30, Issue 11

Abstract: B-Raf kinase inhibitors such as vemurafenib (PLX4032) and dabrafenib have limited therapeutic efficacy on BRAF-mutated thyroid cancer. Cancer stem cells (CSCs) play important roles in tumor recurrence, drug resistance, and metastasis. Whether CSCs play a ...

Abstract	B-Raf kinase inhibitors such as vemurafenib (PLX4032) and dabrafenib have limited therapeutic efficacy on BRAF-mutated thyroid cancer. Cancer stem cells (CSCs) play important roles in tumor recurrence, drug resistance, and metastasis. Whether CSCs play a role in dampening the antitumor activity of B-Raf kinase inhibitors remains unknown. Here, we report that vemurafenib (PLX4032) induced the expression of several stemness-related genes including Gli1, Snail, BMI1, and SOX2 in two anaplastic thyroid cancer cell lines, SW1736 and 8505C, but decreased the expression of these genes in A375 cells, a human melanoma cell line. PLX4032 promoted thyroid cancer stem cell self-renewal, as evidenced by increased numbers of aldehyde dehydrogenase-positive cells and thyrospheres. Mechanistically, PLX4032 activates the PI-3 and mitogen-activated protein kinase pathways through HER3 to cross-activate Gli1, a transcription factor of the sonic hedgehog (Shh) pathway. GANT61, a specific inhibitor of Gli1, blocked the expression of the stemness-related genes in PLX4032-treated thyroid cancer cells in vitro and in vivo in two thyroid cancer xenograft models. GANT61 treatment alone weakly inhibited SW1736 tumor growth but enhanced the antitumor activity of PLX4032 when used in combination. Our study provides mechanistic insights into how thyroid cancer poorly responds to B-Raf kinase inhibitors and suggests that targeting B-Raf and the Shh pathway in combination may overcome thyroid cancer drug resistance.
MeSH term(s)	Humans ; Vemurafenib/pharmacology ; Vemurafenib/therapeutic use ; Hedgehog Proteins ; Proto-Oncogene Proteins B-raf/genetics ; Zinc Finger Protein GLI1/genetics ; Zinc Finger Protein GLI1/therapeutic use ; Cell Self Renewal ; Sulfonamides/pharmacology ; Sulfonamides/therapeutic use ; Indoles/pharmacology ; Indoles/therapeutic use ; Cell Line, Tumor ; Neoplasm Recurrence, Local/drug therapy ; Thyroid Neoplasms/genetics ; Protein Kinase Inhibitors/therapeutic use
Chemical Substances	Vemurafenib (207SMY3FQT) ; Hedgehog Proteins ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; Zinc Finger Protein GLI1 ; Sulfonamides ; Indoles ; Protein Kinase Inhibitors
Language	English
Publishing date	2023-09-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1218450-0
ISSN	1479-6821 ; 1351-0088
ISSN (online)	1479-6821
ISSN	1351-0088
DOI	10.1530/ERC-22-0392
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 4192: Show issues

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Article ; Online: Leflunomide alleviates obesity via activation of the TAK1-AMPK pathway and induction of lipophagy.

Ji, Xiaoyue / Chen, Junhong / You, Chaoying / Sun, Jing / Xu, Xiulong

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2023 Volume 37, Issue 11, Page(s) e23227

Abstract: Lipophagy is a subset of selective autophagy that specifically degrades lipid droplets and plays an important role in obesity. Leflunomide treatment in rheumatoid arthritis (RA) patients has been associated with weight loss and decreased blood glucose ... ...

Abstract	Lipophagy is a subset of selective autophagy that specifically degrades lipid droplets and plays an important role in obesity. Leflunomide treatment in rheumatoid arthritis (RA) patients has been associated with weight loss and decreased blood glucose levels, which cannot be attributed to its known side effects. Our prior studies showed that A77 1726, the active metabolite of leflunomide, acts as an inhibitor of S6K1 to sensitize the insulin receptor and control hyperglycemia. Whether the anti-obesity effect of leflunomide is mediated by targeting S6K1 and its underlying mechanisms remain unclear. Here, we report that A77 1726 induced LC3 lipidation and increased the formation of autophagosomes and lipoautolysosomes in 3T3-L1 adipocytes by activating TGF-β-activated kinase 1 (TAK1), AMP-activated kinase (AMPK), and Unc-51 like autophagy-activated kinase 1 (ULK1). A77 1726 reduced the content of lipid droplets in 3T3-L1 adipocytes, which was blocked by bafilomycin or by beclin-1 knockdown. Similar observations were made in murine adipocytes differentiated from S6K1
MeSH term(s)	Mice ; Humans ; Animals ; Leflunomide/pharmacology ; AMP-Activated Protein Kinases/metabolism ; Autophagy ; Obesity/drug therapy
Chemical Substances	teriflunomide (1C058IKG3B) ; MAP kinase kinase kinase 7 (EC 2.7.11.25) ; Leflunomide (G162GK9U4W) ; AMP-Activated Protein Kinases (EC 2.7.11.31)
Language	English
Publishing date	2023-10-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.202301162R
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Zs.A 2266: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 296: Show issues

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Article ; Online: Xanthine oxidoreductase mediates genotoxic drug-induced autophagy and apoptosis resistance by uric acid accumulation and TGF-β-activated kinase 1 (TAK1) activation.

Wang, Jingxiang / Hu, Yanhua / Liu, Penggang / Xu, Xiulong

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2022 Volume 37, Issue 2, Page(s) e22723

Abstract: Autophagy is a highly conserved cellular process that profoundly impacts the efficacy of genotoxic chemotherapeutic drugs. TGF-β-activated kinase 1 (TAK1) is a serine/threonine kinase that activates several signaling pathways involved in inducing ... ...

Abstract	Autophagy is a highly conserved cellular process that profoundly impacts the efficacy of genotoxic chemotherapeutic drugs. TGF-β-activated kinase 1 (TAK1) is a serine/threonine kinase that activates several signaling pathways involved in inducing autophagy and suppressing cell death. Xanthine oxidoreductase (XOR) is a rate-limiting enzyme that converts hypoxanthine to xanthine, and xanthine to uric acid and hydrogen peroxide in the purine catabolism pathway. Recent studies showed that uric acid can bind to TAK1 and prolong its activation. We hypothesized that genotoxic drugs may induce autophagy and apoptosis resistance by activating TAK1 through XOR-generated uric acid. Here, we report that gemcitabine and 5-fluorouracil (5-FU), two genotoxic drugs, induced autophagy in HeLa and HT-29 cells by activating TAK1 and its two downstream kinases, AMP-activated kinase (AMPK) and c-Jun terminal kinase (JNK). XOR knockdown and the XOR inhibitor allopurinol blocked gemcitabine-induced TAK1, JNK, AMPK, and Unc51-like kinase 1 (ULK1)
MeSH term(s)	Humans ; Uric Acid/pharmacology ; Uric Acid/metabolism ; Xanthine Dehydrogenase/genetics ; Xanthine Dehydrogenase/metabolism ; Allopurinol ; AMP-Activated Protein Kinases/metabolism ; MAP Kinase Kinase Kinases/metabolism ; Autophagy ; DNA Damage ; Apoptosis
Chemical Substances	MAP kinase kinase kinase 7 (EC 2.7.11.25) ; Uric Acid (268B43MJ25) ; Xanthine Dehydrogenase (EC 1.17.1.4) ; Allopurinol (63CZ7GJN5I) ; AMP-Activated Protein Kinases (EC 2.7.11.31) ; MAP Kinase Kinase Kinases (EC 2.7.11.25)
Language	English
Publishing date	2022-12-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.202201436R
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Zs.A 2266: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 296: Show issues

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Article ; Online: Porcine epidemic diarrhoea virus (PEDV) infection activates AMPK and JNK through TAK1 to induce autophagy and enhance virus replication.

Wang, Jingxiang / Kan, Xianjin / Li, Xiaomei / Sun, Jing / Xu, Xiulong

Virulence

2022 Volume 13, Issue 1, Page(s) 1697–1712

Abstract: Autophagy plays an important role in defending against invading microbes. However, numerous viruses can subvert autophagy to benefit their replication. Porcine epidemic diarrhoea virus (PEDV) is an aetiological agent that causes severe porcine epidemic ... ...

Abstract	Autophagy plays an important role in defending against invading microbes. However, numerous viruses can subvert autophagy to benefit their replication. Porcine epidemic diarrhoea virus (PEDV) is an aetiological agent that causes severe porcine epidemic diarrhoea. How PEDV infection regulates autophagy and its role in PEDV replication are inadequately understood. Herein, we report that PEDV induced complete autophagy in Vero and IPEC-DQ cells, as evidenced by increased LC3 lipidation, p62 degradation, and the formation of autolysosomes. The lysosomal protease inhibitors chloroquine (CQ) or bafilomycin A and Beclin-1 or ATG5 knockdown blocked autophagic flux and inhibited PEDV replication. PEDV infection activated AMP-activated protein kinase (AMPK) and c-Jun terminal kinase (JNK) by activating TGF-beta-activated kinase 1 (TAK1). Compound C (CC), an AMPK inhibitor, and SP600125, a JNK inhibitor, inhibited PEDV-induced autophagy and virus replication. AMPK activation led to increased ULK1<sup>S777</sup> phosphorylation and activation. Inhibition of ULK1 activity by SBI-0206965 (SBI) and TAK1 activity by 5Z-7-Oxozeaenol (5Z) or by TAK1 siRNA led to the suppression of autophagy and virus replication. Our study provides mechanistic insights into PEDV-induced autophagy and how PEDV infection leads to JNK and AMPK activation.
MeSH term(s)	AMP-Activated Protein Kinases/genetics ; AMP-Activated Protein Kinases/metabolism ; Animals ; Autophagy ; Beclin-1 ; Chloroquine ; MAP Kinase Kinase Kinases ; Porcine epidemic diarrhea virus/physiology ; Protease Inhibitors ; RNA, Small Interfering ; Swine ; Virus Replication
Chemical Substances	Beclin-1 ; Protease Inhibitors ; RNA, Small Interfering ; Chloroquine (886U3H6UFF) ; MAP Kinase Kinase Kinases (EC 2.7.11.25) ; MAP kinase kinase kinase 7 (EC 2.7.11.25) ; AMP-Activated Protein Kinases (EC 2.7.11.31)
Language	English
Publishing date	2022-09-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2657572-3
ISSN	2150-5608 ; 2150-5594
ISSN (online)	2150-5608
ISSN	2150-5594
DOI	10.1080/21505594.2022.2127192
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: BRAF mutation: a double-edged sword in epigenetic alterations?

Xu, Xiulong

Cell cycle (Georgetown, Tex.)

2012 Volume 11, Issue 3, Page(s) 434–435

MeSH term(s)	DNA Methylation ; Humans ; Melanoma/genetics ; Mutant Proteins/genetics ; Proto-Oncogene Proteins B-raf/genetics
Chemical Substances	Mutant Proteins ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1)
Language	English
Publishing date	2012-02-01
Publishing country	United States
Document type	News ; Comment
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.4161/cc.11.3.19170
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Zs.A 5881: Show issues

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Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

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Article: Long Non-Coding RNA UCA1 Modulates Paclitaxel Resistance in Breast Cancer via miR-613/CDK12 Axis.

Liu, Chunhong / Jiang, Feng / Zhang, Xueqin / Xu, Xiulong

Cancer management and research

2020 Volume 12, Page(s) 2777–2788

Abstract: Background: Paclitaxel (PTX) occupies a considerable status in the chemotherapies of breast cancer (BC), but the drug resistance keeps an obstructive factor of PTX treatment. This study was designed to explore the molecular mechanism of long non-coding ... ...

Abstract	Background: Paclitaxel (PTX) occupies a considerable status in the chemotherapies of breast cancer (BC), but the drug resistance keeps an obstructive factor of PTX treatment. This study was designed to explore the molecular mechanism of long non-coding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1) in PTX resistance of BC. Methods: UCA1, microRNA-613 (miR-613) and cyclin-dependent kinase 12 (CDK12) expression was assayed through quantitative real-time polymerase chain reaction (qRT-PCR). Cell Counting Kit-8 (CCK-8) assay was implemented for evaluating the half inhibitory concentrations (IC Results: UCA1 expressed highly in PTX-resistant BC tissues and cells and regulated PTX resistance in BC cells by affecting cell viability and apoptosis in part. UCA1 negatively interacted with miR-613 and modulated PTX resistance via sponging miR-613. CDK12 was a downstream gene of miR-613 and miR-613 exerted the modulation of PTX resistance via targeting CDK12. Furthermore, UCA1 regulated CDK12 level through interacting with miR-613. The regulatory role of UCA1 in PTX resistance of BC was achieved by miR-613/CDK12 axis in vivo. Conclusion: UCA1 mediated PTX resistance in BC through the miR-613/CDK12 axis, manifesting that UCA1 might improve the PTX treatment of BC as a significant therapeutic biomarker.
Language	English
Publishing date	2020-04-23
Publishing country	New Zealand
Document type	Journal Article
ZDB-ID	2508013-1
ISSN	1179-1322
ISSN	1179-1322
DOI	10.2147/CMAR.S241969
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: The A179L Gene of African Swine Fever Virus Suppresses Virus-Induced Apoptosis but Enhances Necroptosis.

Shi, Jun / Liu, Wei / Zhang, Miao / Sun, Jing / Xu, Xiulong

Viruses

2021 Volume 13, Issue 12

Abstract: A179L, a non-structural protein of African swine fever virus (ASFV), is capable of suppressing apoptosis by binding the BH3 domain of the pro-apoptotic Bcl-2 family proteins via a conserved ligand binding groove. Our present study aims to determine if ... ...

Abstract	A179L, a non-structural protein of African swine fever virus (ASFV), is capable of suppressing apoptosis by binding the BH3 domain of the pro-apoptotic Bcl-2 family proteins via a conserved ligand binding groove. Our present study aims to determine if A179L affects necroptosis, the second form of programmed cell death induced by DNA and RNA viruses. Here we report that A179L enhanced TNF-α or TSZ (TNF-α, Smac, and Z-Vad)-induced receptor-interacting protein kinase (RIPK1), RIPK3, and mixed lineage kinase domain like peudokinase (MLKL) phosphorylation in L929 cells, a murine fibrosarcoma cell line. Sytox green staining revealed that A179L significantly increased the number of necroptotic cells in TSZ-treated L929 cells. Using human herpes simplex virus 1 (HSV-1) to model DNA virus-induced cell death, we found that A179L blocked the HSV-1-induced cleavage of poly (ADP-ribose) polymerase (PARP), caspase 8, and caspase 3 and decreased the number of apoptotic cells in HSV-1-infected IPEC-DQ cells, a porcine intestinal epithelial cell line. In contrast, A179L transfection of IPEC-DQ cells enhanced HSV-1-induced RIPK1, RIPK3, and MLKL phosphorylation and increased the number of necroptotic cells. Consistently, A179L also suppressed apoptosis but enhanced the necroptosis induced by two RNA viruses, Sendai virus (SeV) and influenza virus (IAV). Our study uncovers a previously unrecognized role of A179L in regulating cell death and suggests that A179L re-directs its anti-apoptotic activity to necroptosis.
MeSH term(s)	African Swine Fever/genetics ; African Swine Fever/metabolism ; African Swine Fever/physiopathology ; African Swine Fever/virology ; African Swine Fever Virus/genetics ; African Swine Fever Virus/metabolism ; Animals ; Apoptosis ; Apoptosis Regulatory Proteins/genetics ; Apoptosis Regulatory Proteins/metabolism ; Caspase 3/genetics ; Caspase 3/metabolism ; Caspase 8/genetics ; Caspase 8/metabolism ; Host-Pathogen Interactions ; Necroptosis ; Phosphorylation ; Protein Kinases/genetics ; Protein Kinases/metabolism ; Swine ; Tumor Necrosis Factor-alpha/genetics ; Tumor Necrosis Factor-alpha/metabolism ; Viral Proteins/genetics ; Viral Proteins/metabolism
Chemical Substances	A179L protein, African Swine Fever Virus ; Apoptosis Regulatory Proteins ; Tumor Necrosis Factor-alpha ; Viral Proteins ; Protein Kinases (EC 2.7.-) ; Caspase 3 (EC 3.4.22.-) ; Caspase 8 (EC 3.4.22.-)
Language	English
Publishing date	2021-12-13
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v13122490
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Uric acid accumulation in DNA-damaged tumor cells induces NKG2D ligand expression and antitumor immunity by activating TGF-β-activated kinase 1.

Wang, Jingxiang / Liu, Kai / Xiao, Tianxiang / Liu, Penggang / Prinz, Richard A / Xu, Xiulong

Oncoimmunology

2022 Volume 11, Issue 1, Page(s) 2016159

Abstract: DNA damage by genotoxic drugs such as gemcitabine and 5-fluorouracil (5-FU) activates the ataxia telangiectasia, mutated (ATM)-Chk pathway and induces the expression of NKG2D ligands such as the MHC class I-related chain A and B (MICA/B). The mechanisms ... ...

Abstract	DNA damage by genotoxic drugs such as gemcitabine and 5-fluorouracil (5-FU) activates the ataxia telangiectasia, mutated (ATM)-Chk pathway and induces the expression of NKG2D ligands such as the MHC class I-related chain A and B (MICA/B). The mechanisms underlying this remain incompletely understood. Here we report that xanthine oxidoreductase (XOR), a rate-limiting enzyme that produces uric acid in the purine catabolism pathway, promotes DNA damage-induced MICA/B expression. Inhibition of the ATM-Chk pathway blocks genotoxic drug-induced uric acid production, TGF-β-activated kinase 1 (TAK1) activation, ERK phosphorylation, and MICA/B expression. Inhibition of uric acid production by the XOR inhibitor allopurinol blocks DNA damage-induced TAK1 activation and MICA/B expression in genotoxic drug-treated cells. Exogenous uric acid activates TAK1, NF-κB, and the MAP kinase pathway. TAK1 inhibition blocks gemcitabine- and uric acid-induced MAP kinase activation and MICA/B expression. Exogenous uric acid in its salt form, monosodium urate (MSU), induces MICA/B expression and sensitizes tumor cells to NK cell killing. MSU immunization with irradiated murine breast cancer cell line RCAS-Neu retards breast cancer growth in syngeneic breast cancer models and delays breast cancer development in a somatic breast cancer model. Our study suggests that uric acid accumulation plays an important role in activating TAK1, inducing DNA damage-induced MICA/B expression, and enhancing antitumor immunity.
MeSH term(s)	Animals ; DNA ; DNA Damage ; Ligands ; MAP Kinase Kinase Kinases ; Mice ; NK Cell Lectin-Like Receptor Subfamily K/genetics ; NK Cell Lectin-Like Receptor Subfamily K/metabolism ; Uric Acid/pharmacology
Chemical Substances	Ligands ; NK Cell Lectin-Like Receptor Subfamily K ; Uric Acid (268B43MJ25) ; DNA (9007-49-2) ; MAP Kinase Kinase Kinases (EC 2.7.11.25) ; MAP kinase kinase kinase 7 (EC 2.7.11.25)
Language	English
Publishing date	2022-01-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2645309-5
ISSN	2162-402X ; 2162-4011
ISSN (online)	2162-402X
ISSN	2162-4011
DOI	10.1080/2162402X.2021.2016159
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: The A179L Gene of African Swine Fever Virus Suppresses Virus-Induced Apoptosis but Enhances Necroptosis

Shi, Jun / Liu, Wei / Zhang, Miao / Sun, Jing / Xu, Xiulong

Viruses. 2021 Dec. 13, v. 13, no. 12

2021

Abstract	A179L, a non-structural protein of African swine fever virus (ASFV), is capable of suppressing apoptosis by binding the BH3 domain of the pro-apoptotic Bcl-2 family proteins via a conserved ligand binding groove. Our present study aims to determine if A179L affects necroptosis, the second form of programmed cell death induced by DNA and RNA viruses. Here we report that A179L enhanced TNF-α or TSZ (TNF-α, Smac, and Z-Vad)-induced receptor-interacting protein kinase (RIPK1), RIPK3, and mixed lineage kinase domain like peudokinase (MLKL) phosphorylation in L929 cells, a murine fibrosarcoma cell line. Sytox green staining revealed that A179L significantly increased the number of necroptotic cells in TSZ-treated L929 cells. Using human herpes simplex virus 1 (HSV-1) to model DNA virus-induced cell death, we found that A179L blocked the HSV-1-induced cleavage of poly (ADP-ribose) polymerase (PARP), caspase 8, and caspase 3 and decreased the number of apoptotic cells in HSV-1-infected IPEC-DQ cells, a porcine intestinal epithelial cell line. In contrast, A179L transfection of IPEC-DQ cells enhanced HSV-1-induced RIPK1, RIPK3, and MLKL phosphorylation and increased the number of necroptotic cells. Consistently, A179L also suppressed apoptosis but enhanced the necroptosis induced by two RNA viruses, Sendai virus (SeV) and influenza virus (IAV). Our study uncovers a previously unrecognized role of A179L in regulating cell death and suggests that A179L re-directs its anti-apoptotic activity to necroptosis.
Keywords	African swine fever virus ; DNA ; Human alphaherpesvirus 1 ; Murine respirovirus ; Orthomyxoviridae ; RNA ; apoptosis ; caspase-3 ; caspase-8 ; cell lines ; epithelial cells ; fibrosarcoma ; genes ; humans ; ligands ; mice ; necroptosis ; phosphorylation ; protein kinases ; swine ; transfection ; viral nonstructural proteins
Language	English
Dates of publication	2021-1213
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2516098-9
ISSN	1999-4915
ISSN	1999-4915
DOI	10.3390/v13122490
Database	NAL-Catalogue (AGRICOLA)

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Article: Restriction of intracellular Salmonella typhimurium growth by the small-molecule autophagy inducer A77 1726 through the activation of the AMPK-ULK1 axis

Zhuang, Jing / Ji, Xiaoyue / Zhu, Yue / Liu, Wei / Sun, Jing / Jiao, Xinan / Xu, Xiulong

Veterinary microbiology. 2021 Mar., v. 254

2021

Abstract: Autophagy plays an important role in restricting the growth of invading intracellular microbes. Salmonella (S) Typhimurium, an intracellular pathogen that causes gastroenteritis and food poisoning in humans, evades autophagic detection by multiple ... ...

Abstract	Autophagy plays an important role in restricting the growth of invading intracellular microbes. Salmonella (S) Typhimurium, an intracellular pathogen that causes gastroenteritis and food poisoning in humans, evades autophagic detection by multiple mechanisms. There has been growing interest in developing autophagy inducers as novel antimicrobial agents for treating intracellular bacterial infections. We recently reported that A77 1726, the active metabolite of the anti-inflammatory drug leflunomide, induces autophagy by activating AMP-activated protein kinase (AMPK) and Unc-51 like autophagy activating kinase 1 (ULK1). Our present study aims to determine if A77 1726 was able to restrict intracellular Salmonella growth by inducing autophagy. We first confirmed the ability of A77 1726 to induce autophagy by activating the AMPK-ULK1 axis in uninfected RAW264.7 (a murine macrophage cell line) and HeLa cells (a human cervical carcinoma cell line). A77 1726 enhanced autophagy in S. Typhimurium-infected cells, as evidenced by increased levels of LC3 lipidation and increased numbers of autophagosomes and autolysosomes. Confocal microscopy revealed that A77 1726 induced xenophagy in macrophages, as evidenced by an increased number of LC3-coated bacteria in the cytoplasm. A77 1726 significantly decreased the number of intracellular S. Typhimurium in macrophages. Taken together, our study has demonstrated the ability of A77 1726 to restrict intracellular S. Typhimurium growth in vitro by enhancing xenophagy.
Keywords	AMP-activated protein kinase ; Salmonella Typhimurium ; anti-inflammatory agents ; autophagosomes ; confocal microscopy ; gastroenteritis ; humans ; macroautophagy ; macrophages ; metabolites ; mice ; neoplasm cells ; pathogens ; uterine cervical neoplasms
Language	English
Dates of publication	2021-03
Publishing place	Elsevier B.V.
Document type	Article
Note	NAL-light
ZDB-ID	753154-0
ISSN	1873-2542 ; 0378-1135
ISSN (online)	1873-2542
ISSN	0378-1135
DOI	10.1016/j.vetmic.2021.108982
Database	NAL-Catalogue (AGRICOLA)

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Zs.A 2917: Show issues

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