ELIZA

return kwic search for increase out of >500 occurrences
611425 occurrences (No.13 in the rank) during 5 years in the PubMed. [cache]

18) TAS4464 activated both caspase-8 and caspase-9 along with an increase in NOXA and a decrease in c-FLIP, resulting in complete tumor remission in a human AML xenograft model.

--- ABSTRACT ---

PMID:33420360 DOI:10.1038/s41388-020-01586-4

2021 Oncogene

* TAS4464, a NEDD8-activating enzyme inhibitor, activates both intrinsic and extrinsic apoptotic pathways via c-Myc-mediated regulation in acute myeloid leukemia.

- TAS4464, a potent, selective small molecule NEDD8-activating enzyme (NAE) inhibitor, leads to inactivation of cullin-RING E3 ubiquitin ligases (CRLs) and consequent accumulations of its substrate proteins. Here, we investigated the antitumor properties and action mechanism of TAS4464 in acute myeloid leukemia (AML). TAS4464 induced apoptotic cell death in various AML cell lines. TAS4464 treatments resulted in the activation of both the caspase-9-mediated intrinsic apoptotic pathway and caspase-8-mediated extrinsic apoptotic pathway in AML cells; combined treatment with inhibitors of these caspases markedly diminished TAS4464-induced apoptosis. In each apoptotic pathway, TAS4464 induced the mRNA transcription of the intrinsic proapoptotic factor NOXA and decreased that of the extrinsic antiapoptotic factor c-FLIP. RNA-sequencing analysis showed that the signaling pathway of the CRL substrate c-Myc was enriched after TAS4464 treatment. Chromatin immunoprecipitation (ChIP) assay revealed that TAS4464-induced c-Myc bound to the PMAIP1 (encoding NOXA) and CFLAR (encoding c-FLIP) promoter regions, and siRNA-mediated c-Myc knockdown neutralized both TAS4464-mediated NOXA induction and c-FLIP downregulation. TAS4464 activated both caspase-8 and caspase-9 along with an increase in NOXA and a decrease in c-FLIP, resulting in complete tumor remission in a human AML xenograft model. These findings suggest that NAE inhibition leads to anti-AML activity via a novel c-Myc-dependent apoptosis induction mechanism.

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(1)204 in	(7)5 was	(13)3 health	(19)2 range
(2)67 the	(8)4 their	(14)3 on	(20)2 significantly
(3)31 of	(9)4 with	(15)2 null	(21)2 tumor
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(5)6 risk	(11)3 access	(17)2 muscle
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--- WordNet output for increase --- =>大きくなる, を増す, 増大させる, 強まる, 増加, 増える, 増やす Overview of noun increase The noun increase has 5 senses (first 5 from tagged texts) 1. (49) addition, increase, gain -- (a quantity that is added; "there was an addition to property taxes this year"; "they recorded the cattle's gain in weight over a period of weeks") 2. (21) increase -- (a change resulting in an increase; "the increase is scheduled for next month") 3. (7) increase, increment, growth -- (a process of becoming larger or longer or more numerous or more important; "the increase in unemployment"; "the growth of population") 4. (3) increase, increment -- (the amount by which something increases; "they proposed an increase of 15 percent in the fare") 5. (3) increase, step-up -- (the act of increasing something; "he gave me an increase in salary") Overview of verb increase The verb increase has 2 senses (first 2 from tagged texts) 1. (86) increase -- (become bigger or greater in amount; "The amount of work increased") 2. (61) increase -- (make bigger or more; "The boss finally increased her salary"; "The university increased the number of students it admitted") --- WordNet end ---