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001-es BibID:	BIBFORM103842
035-os BibID:	(Scopus)85129934393 (cikkazonosító)e0268217
Első szerző:	Bohusné Barta Bettina
Cím:	Survival of HT29 cancer cells is influenced by hepatocyte growth factor receptor inhibition through modulation of self-DNA-triggered TLR9-dependent autophagy response / Bettina Bohusné Barta, Ágnes Simon, Lőrinc Nagy, Titanilla Dankó, Regina Eszter Raffay, Gábor Petővári, Viktória Zsiros, Anna Sebestyén, Ferenc Sipos, Györgyi Műzes
Dátum:	2022
ISSN:	1932-6203
Megjegyzések:	HGFR activation drives the malignant progression of colorectal cancer, and its inhibition displays anti-autophagic activity. The interrelated role of HGFR inhibition and TLR9/autophagy signaling in HT29 cancer cells subjected to modified self-DNA treatments has not been clarified. We analyzed this complex interplay with cell metabolism and proliferation measurements, TLR9, HGFR and autophagy inhibitory assays and WES Simple Western blot-based autophagy flux measurements, gene expression analyses, immunocytochemistry, and transmission electron microscopy. The overexpression of MyD88 and caspase-3 was associated with enhanced HT29 cell proliferation, suggesting that incubation with self-DNAs could suppress the apoptosis-induced compensatory cell proliferation. HGFR inhibition blocked the proliferation-reducing effect of genomic and hypermethylated, but not that of fragmented DNA. Lowest cell proliferation was achieved with the concomitant use of genomic DNA, HGFR inhibitor, and chloroquine, when the proliferation stimulating effect of STAT3 overexpression could be outweighed by the inhibitory effect of LC3B, indicating the putative involvement of HGFR-mTOR-ULK1 molecular cascade in HGFR inhibitor-mediated autophagy. The most intense cell proliferation was caused by the co-administration of hypermethylated DNA, TLR9 and HGFR inhibitors, when decreased expression of both canonical and non-canonical HGFR signaling pathways and autophagy-related genes was present. The observed ultrastructural changes also support the context-dependent role of HGFR inhibition and autophagy on cell survival and proliferation. Further investigation of the influence of the studied signaling pathways and cellular processes can provide a basis for novel, individualized anti-cancer therapies.
Tárgyszavak:	Orvostudományok Egészségtudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk
Megjelenés:	Plos One. - 17 : 5 (2022), p. 1-25. -
További szerzők:	Simon Ágnes Nagy Lőrinc (1995-) (biológus, gyógyszer-biotechnológus) Dankó Titanilla Raffay Regina Eszter Petővári Gábor Zsiros Viktória Sebestyén Anna Sipos Ferenc (belgyógyász) Műzes Györgyi
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001-es BibID:	BIBFORM114860
Első szerző:	Műzes Györgyi
Cím:	IGF1R inhibition affects the survival of HT29 cancer cells by alterations of the TLR9- and autophagy signaling / G. Műzes, A. Sebestyén, Á. Simon, L. Nagy, B. Barta, T. Dankó, A. L. Kiss, F. J. Sipos
Dátum:	2019
ISSN:	0923-7534 1569-8041
Megjegyzések:	Background In HT29 cells, an interplay between self-DNA-induced TLR9-signaling and autophagy response was found with significant effects on cell survival and kinetic parameters. The IGF/IGF1R system plays a determinant role in the pathogenesis and progression of colorectal cancer. This pathway is upstream of mTORC1, a negative regulator of autophagy. I mammalian systems chronic IGF1R inhibition was shown to attenuate autophagosome formation. The interrelated action of IGF1R inhibition and TLR9/autophagy signaling in cancer cells has not yet been clarified. The present study was designed to assess this complex network using HT29 colon carcinoma cells. Methods HT29 cells were incubated for 72 h with genomic (g), hypermethylated (m), and fragmented (f) tumor self-DNAs, and with/without inhibitors of IGF1R (picropodophyllin), autophagy (chloroquine) and TLR9 (ODN2088), respectively. Cell viability was measured by MTT assay. Transcriptional changes of TLR9-signaling, IGF1R, mTORC, Akt, and the autophagy process were assayed by Human v3 miRNA Assay (NanoString). Autophagy proteins were detected by immunocytochemistry, while morphology of apoptosis and autophagy by transmission electron microscopy (TEM). Results In case of autophagy g- and f-DNAs caused significant upregulation of Beclin1, Atg16L1, LC3 mRNAs, and downregulation of mTORC, and Akt, verified by immunocytochemistry, as well. IGF1R-inhibition alone altered inversely the autophagy-associated gene- and protein-expressions. Upon combined inhibition of autophagy, TLR9 and/or IGF1R-signaling varying degree of autophagy was detected in all groups of tumor cells according to NanoString and TEM. Incubation with IGF1R inhibitor and with m-DNA no expected suppression of tumor cell survival, induction of apoptotic death, and activation of mitophagy were found. Moreover, IGF1R inhibition affected negatively the cell-protective effect f-DNA on macroautophagy and lipophagy. Conclusions Our study provided evidence for an interaction between the inhibited IGF1R and TLR9/autophagy signaling with major influences on survival, proliferation and death of HT29 cells subjected to intact/modified self-DNAs. (Funded by StartUp.). Legal entity responsible for the study Ferenc Sipos. Funding StartUp. Disclosure All authors have declared no conflicts of interest.
Tárgyszavak:	Orvostudományok Klinikai orvostudományok idézhető absztrakt folyóiratcikk
Megjelenés:	Annals Of Oncology. - 30 : Suppl_5 (2019), p. 806-807. -
További szerzők:	Sebestyén Andor Simon Ágnes Nagy Lőrinc (1995-) (biológus, gyógyszer-biotechnológus) Barta Bianka Danko Tamás Kiss A. L. Sipos F. J.
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001-es BibID:	BIBFORM114861
Első szerző:	Sipos F. J.
Cím:	Modulation of TLR9-dependent autophagy response via inhibition of c-Met signaling influences the survival of HT29 cancer cells / F. J. Sipos, L. Nagy, B. Barta, Á. Simon, T. Dankó, A. Sebestyén, A. L. Kiss, G. Műzes
Dátum:	2019
ISSN:	0923-7534 1569-8041
Megjegyzések:	Background:InHT29cells,aninterplaybetweenself-DNA-inducedTLR9-and autophagyresponseswasfoundwithremarkableeffectsonsurvivalanddifferentiation oftumorcells.c-Metactivationisknowntodrivetheprogressionofcolorectalcancer bypromotingsignalingcascadesthatmainlyresultinalterationsofcellmotility,survivalandproliferation.c-Metinhibitionwasshowntoinhibitautophagy.Incancer cellstheinterrelatedroleofc-MetinhibitionandTLR9/autophagysignalinghasnotyet beenclarified,soweaimedtoassessthiscomplexinterplay. Methods:HT29cellswereincubatedfor72hwithgenomic(g),hypermethylated(m), andfragmented(f)tumorself-DNAs,andwith/withoutinhibitorsofc-Met(diisothiocyanatostilbene),autophagy(chloroquine)andTLR9(ODN2088),respectively.Cell viabilitywasmeasuredbyMTTassay.TranscriptionalchangesofTLR9-signaling, PI3K,CD95,c-Met,Bcl2,cytochrome-c,andtheautophagyprocesswereassayedby Humanv3miRNAAssay(NanoString).Autophagyproteinsweredetectedbyimmunocytochemistry,whilemorphologyofapoptosisandautophagybytransmissionelectronmicroscopy(TEM). Results:Self-DNAsgandfresultedinsignificantupregulationofBeclin1,Atg16L1, LC3mRNAs,anddownregulationofPI3K,Bcl2,CD95,andcytochrome-c,verifiedby immunocytochemistry,aswell.c-Metinhibitionalonealteredinverselytheautophagyassociatedgene-andprotein-expressions.Ineachgroupoftumorcellsusingcombined inhibitionofautophagy,TLR9and/orc-Met-signalingvaryingdegreeofautophagy wasobservedaccordingtoNanoStringandTEM.Followingcombinedincubationwith c-Metinhibitorandm-DNAsnoexpectedsuppressionoftumorcellsurvivaland inductionofapoptosisandmitophagyweredetected.Further,c-Metinhibition changedthecell-protectiveeffectf-DNAonmacroautophagy. Conclusions:Ourstudyprovidedevidenceforanintensecrosstalkbetweentheinhibitedc-Metcanonicalandnon-canonicalsignalingpathways,andtheTLR9/autophagy responsewithprofoundimpactsonsurvival,proliferationanddeathofHT29cellssubjectedtointact/modifiedself-DNAs. Legalentityresponsibleforthestudy:FerencSipos. Funding:StartUp. Disclosure:Allauthorshavedeclarednoconflictsofinterest.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idézhető absztrakt folyóiratcikk
Megjelenés:	Annals Of Oncology. - 30 : Suppl_5 (2019), p. v807. -
További szerzők:	Nagy Lőrinc (1995-) (biológus, gyógyszer-biotechnológus) Barta Bianka Simon Ágnes Danko Tamás Sebestyén Andor Kiss A. L. Műzes Györgyi
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001-es BibID:	BIBFORM103847
035-os BibID:	(Scopus)85131270901 (cikkazonosító)1610322 (WOS)000802697500001
Első szerző:	Sipos Ferenc
Cím:	Survival of HT29 Cancer Cells Is Affected by IGF1R Inhibition via Modulation of Self-DNA-Triggered TLR9 Signaling and the Autophagy Response / Ferenc Sipos, Bettina Bohusné Barta, Ágnes Simon, Lőrinc Nagy, Titanilla Dankó, Regina Eszter Raffay, Gábor Petővári, Viktória Zsiros, Barnabás Wichmann, Anna Sebestyén, Györgyi Műzes
Dátum:	2022
ISSN:	1219-4956 1532-2807
Megjegyzések:	Purpose: In HT29 colon cancer cells, a close interplay between self-DNA-induced TLR9 signaling and autophagy response was found, with remarkable effects on cell survival and differentiation. IGF1R activation drives the development and malignant progression of colorectal cancer. IGF1R inhibition displays a controversial effect on autophagy. The interrelated roles of IGF1R inhibition and TLR9/autophagy signaling in HT29 cancer cells have not yet been clarified. In our study, we aimed to investigate the complex interplay of IGF1R inhibition and TLR9/autophagy signaling in HT29 cells. Methods: HT29 cells were incubated with tumor-originated self-DNA with or without inhibitors of IGF1R (picropodophyllin), autophagy (chloroquine), and TLR9 (ODN2088), respectively. Cell proliferation and metabolic activity measurements, direct cell counting, NanoString and Taqman gene expression analyses, immunocytochemistry, WES Simple Western blot, and transmission electron microscopy investigations were performed. Results: The concomitant use of tumor-derived self-DNA and IGF1R inhibitors displays anti-proliferative potential, which can be reversed by parallel TLR9 signaling inhibition. The distinct effects of picropodophyllin, ODN2088, and chloroquine per se or in combination on HT29 cell proliferation and autophagy suggest that either the IGF1R-associated or non-associated autophagy machinery is "Janus-faced" regarding its actions on cell proliferation. Autophagy, induced by different combinations of self-DNA and inhibitors is not sufficient to rescue HT29 cells from death but results in the survival of some CD133-positive stem-like HT29 cells. Conclusion: The creation of new types of combined IGF1R, autophagy, and/or TLR9 signaling inhibitors would play a significant role in the development of more personalized anti-tumor therapies for colorectal cancer.
Tárgyszavak:	Orvostudományok Egészségtudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk
Megjelenés:	Pathology & Oncology Research. - 28 (2022), p. 1-15. -
További szerzők:	Bohusné Barta Bettina Simon Ágnes Nagy Lőrinc (1995-) (biológus, gyógyszer-biotechnológus) Dankó Titanilla Raffay Regina Eszter Petővári Gábor Zsiros Viktória Wichmann Barnabás Sebestyén Anna Műzes Györgyi
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