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001-es BibID:	BIBFORM084074
035-os BibID:	(cikkazonosító)648 (WoS)000530232300124 (Scopus)85081217936
Első szerző:	Jambrovics Károly (biológus, gyógyszer-biotechnológus)
Cím:	Benefits of Combined All-Trans Retinoic Acid and Arsenic Trioxide Treatment of Acute Promyelocytic Leukemia Cells and Further Enhancement by Inhibition of Atypically Expressed Transglutaminase 2 / Jambrovics Károly, Uray Iván P., Keillor Jeffrey W., Fésüs László, Balajthy Zoltán
Dátum:	2020
ISSN:	2072-6694
Megjegyzések:	Randomized trials in acute promyelocytic leukemia patients have shown that treatment with a combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) is superior in efficacy to monotherapy, with significantly decreased mortality. So far, there are little data available to explain the success of the ATRA and ATO combination treatment in molecular terms. We showed that ATRA- and ATO-treated cells had the same capacity for superoxide production, which was reduced by two-thirds in the combined treatment. Secreted inflammatory biomarkers (monocyte chemoattractant protein-1 [MCP-1], interleukin-1 beta [IL-1?] and tumor necrosis factor-? [TNF-?]) were significantly decreased and were further reduced in a transglutaminase 2 (TG2) expressiondependent manner. The amount of secreted TNF-? in the supernatant of NB4 TG2 knockout cells was close to 50 times lower than in ATRA-treated differentiated wild-type NB4 cells. The irreversible inhibitor of TG2 NC9 not only decreased reactive oxygen species production 28-fold, but decreased the concentration of MCP-1, IL-1? and TNF-? 8-, 15- and 61-fold, respectively in the combined ATRA + ATO-treated wild-type NB4 cell culture. We propose that atypical expression of TG2 leads to the generation of inflammation, which thereby serves as a potential target for the prevention of differentiation syndrome.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk
Megjelenés:	Cancers. - 12 : 3 (2020), p. 648-. -
További szerzők:	Uray Iván Péter (1970-) (kutatóorvos) Keillor, Jeffrey W. Fésüs László (1947-) (orvos biokémikus) Balajthy Zoltán (1957-) (biokémikus, sejtbiológus)
Pályázati támogatás:	GINOP-2.3.2-15-2016-00020 GINOP K129218 OTKA
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
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001-es BibID:	BIBFORM077169
035-os BibID:	(WoS)000460110400026 (Scopus)85063936796
Első szerző:	Jambrovics Károly (biológus, gyógyszer-biotechnológus)
Cím:	Transglutaminase 2 programs differentiating acute promyelocytic leukemia cells in all-trans retinoic acid treatment to inflammatory stage through NF-kB activation / Jambrovics Károly, Uray Iván P., Keresztessy Zsolt, Keillor Jeffrey W., Fésüs László, Balajthy Zoltán
Dátum:	2019
ISSN:	0390-6078
Megjegyzések:	Differentiation syndrome is a life-threatening complication arising during retinoid treatment of acute promyelocytic leukemia. Administration of all-trans retinoic acid leads to significant changes in gene expression, among the most induced of which is transglutaminase 2, which is not normally expressed in neutrophil granulocytes. To evaluate the pathophysiological function of transglutaminase 2 in the context of immunological function and disease outcomes, such as excessive superoxide anion, cytokine, and chemokine production in differentiated NB4 cells, we used an NB4 transglutaminase knock-out cell line and a transglutaminase inhibitor, NC9, which inhibits both transamidase- and guanosine triphosphate-binding activities, to clarify transglutaminase's contribution to the development of potentially lethal differentiation syndrome during all-trans retinoic acid treatment of acute promyelocytic leukemia. We found that such treatment not only enhanced cell-surface expression of CD11b and CD11c but also induced high-affinity states; atypical transglutaminase 2 expression in NB4 cells activated the nuclear factor kappa-light-chain-enhancer of activated B cells pathway, driving pathogenic processes with an inflammatory cascade through the expression of numerous cytokines, including Tumor necrosis factor alpha, Interleukin 1 beta, and Monocyte chemoattractant protein 1. NC9 decreased the amount of transglutaminase 2, p65/RelA, and p50 in differentiated NB4 cells and their nuclei, leading to attenuated inflammatory cytokine synthesis. NC9 significantly inhibits transglutaminase 2 nuclear translocation but accelerates its proteasomal breakdown. This study demonstrates that transglutaminase 2 expression induced by all-trans retinoic acid treatment reprograms inflammatory signaling networks governed by nuclear factor kappa-light-chain-enhancer of activated B cells activation, resulting in over-expression of tumor necrosis factor alpha and Interleukin 1 beta in differentiating acute promyelocytic leukemia cells, suggesting that atypically expressed transglutaminase 2 is a promising target for leukemia treatment.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk
Megjelenés:	Haematologica-The Hematology Journal. - 104 : 3 (2019), p. 505-515. -
További szerzők:	Uray Iván Péter (1970-) (kutatóorvos) Keresztessy Zsolt Keillor, Jeffrey W. Fésüs László (1947-) (orvos biokémikus) Balajthy Zoltán (1957-) (biokémikus, sejtbiológus)
Pályázati támogatás:	GINOP-2.3.2-15-2016-00020 GINOP TÁMOP-4.2.2.D-15/1/KONV-2015-0016 TÁMOP EFOP-3.6.1-16-2016-00022 EFOP GINOP-2.3.2-15-2016-00006 GINOP NK105046 OTKA
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
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