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001-es BibID:	BIBFORM096377
035-os BibID:	(cikkazonosító)8869 (scopus)85112763543 (wos)000689059300001
Első szerző:	Kiss Alexandra (klinikai laboratóriumi kutató)
Cím:	NMNAT1 Is a Survival Factor in Actinomycin D-Induced Osteosarcoma Cell Death / Alexandra Kiss, Csaba Csikos, Zsolt Regdon, Zsuzsanna Polgár, László Virág, Csaba Hegedűs
Dátum:	2021
ISSN:	1661-6596 1422-0067
Megjegyzések:	Osteosarcoma is a frequent and extremely aggressive type of pediatric cancer. New therapeutic approaches are needed to improve the overall survival of osteosarcoma patients. Our previous results suggest that NMNAT1, a key enzyme in nuclear NAD+ synthesis, facilitates the survival of cisplatin-treated osteosarcoma cells. A high-throughput cytotoxicity screening was performed to identify novel pathways or compounds linked to the cancer-promoting role of NMNAT1. Nine compounds caused higher toxicity in the NMNAT1 KO U2OS cells compared to their wild type counterparts, and actinomycin D (ActD) was the most potent. ActD-treatment of NMNAT1 KO cells increased caspase activity and secondary necrosis. The reduced NAD+ content in NMNAT1 KO cells was further decreased by ActD, which partially inhibited NAD+ -dependent enzymes, including the DNA nick sensor enzyme PARP1 and the NAD+ -dependent deacetylase SIRT1. Impaired PARP1 activity increased DNA damage in ActD-treated NMNAT1 knockout cells, while SIRT1 impairment increased acetylation of the p53 protein, causing the upregulation of pro-apoptotic proteins (NOXA, BAX). Proliferation was decreased through both PARP- and SIRT-dependent pathways. On the one hand, PARP inhibitors sensitized wild type but not NMNAT1 KO cells to ActD-induced anti-clonogenic effects; on the other hand, over-acetylated p53 induced the expression of the antiproliferative p21 protein leading to cell cycle arrest. Based on our results, NMNAT1 acts as a survival factor in ActD-treated osteosarcoma cells. By inhibiting both PARP1- and SIRT1-dependent cellular pathways, NMNAT1 inhibition can be a promising new tool in osteosarcoma chemotherapy.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk NAD+ NMNAT1 actinomycin D chemotherapy apoptosis PARP1 SIRT1 osteosarcoma cancer high throughput screening
Megjelenés:	International Journal of Molecular Sciences. - 22 : 16 (2021), p. 1-17. -
További szerzők:	Csíkos Csaba Regdon Zsolt (1988-) (biokémikus, molekuláris biológus) Polgár Zsuzsanna (1978-) (agrármérnök, biotechnológus) Virág László (1965-) (biokémikus, sejtbiológus, farmakológus) Hegedűs Csaba (1980-) (biokémikus, molekuláris biológus)
Pályázati támogatás:	GINOP-2.3.2-15-2016-00020 GINOP GINOP-2.3.2-15-2016-00048 GINOP
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
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