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作者

Wenjing Liu Chunhui Dou Ce Zhang Ping Chen Shu Zhang Renxiang Wang Qing Han Hongyu Zhao Daqi Li

作者单位

²Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, Shandong, China ¹School of Clinical Medicine, Shandong Second Medical University, Weifang 261000, Shandong, China ³Central Hospital Affiliated to Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250013, Shandong, China

刊名

Biochemical Pharmacology

年份

2024

卷号

Vol.230 Part 3

页码

116620

ISSN

0006-2952

关键词

PX-478 Acute myeloid leukemia Hypoxia Apoptotic effect Hypoxia-inducible factor-1alpha Glycogen branching enzyme 1

摘要

Acute myeloid leukemia is a highly heterogeneous hematologic malignancy characterized by limited therapeutic options and a pronounced tendency for relapse. PX-478, a novel inhibitor of hypoxia-inducible factor 1-alpha , has demonstrated antitumor activity across various cancer models, but its specific role in AML remains unexplored. This study aimed to explore the potential target and mechanism of PX-478-induced AML cell apoptosis. First, PX-478 induced AML cell apoptosis in vitro under hypoxia...更多

Acute myeloid leukemia is a highly heterogeneous hematologic malignancy characterized by limited therapeutic options and a pronounced tendency for relapse. PX-478, a novel inhibitor of hypoxia-inducible factor 1-alpha , has demonstrated antitumor activity across various cancer models, but its specific role in AML remains unexplored. This study aimed to explore the potential target and mechanism of PX-478-induced AML cell apoptosis. First, PX-478 induced AML cell apoptosis in vitro under hypoxia via modulation of the Bcl-2 family and activation of the mitochondria-mediated caspase cascade, exhibiting a concentration-dependent effect. Additionally, in vivo administration of PX-478 led to notable inhibition of subcutaneous AML xenograft growth in mice, coupled with increased tumor cell apoptosis. RNA sequencing and cellular studies revealed downregulation of the PI3K/AKT/mTOR signaling pathway in PX-478-treated cells. Consistently, cellular studies also implicated PI3K/AKT/mTOR pathway in PX-478-induced AML cell apoptosis. Furthermore, by screening for RNA sequencing differential genes and subsequent experimental verification, Glycogen branching enzyme 1 may be involved in PX-478-induced apoptosis in AML cells. We found that inhibiting GBE1 expression in AML cells led to downregulation of the PI3K/AKT/mTOR pathway and induced apoptosis. In experiments using AML cells with reduced GBE1 expression , PX-478 treatment did not further downregulate the pathway or enhance apoptosis. Re-expression of GBE1 in shGBE1 cells alleviated apoptosis and reduced PX-478- induced apoptosis and pathway downregulation. In conclusion, our findings provide convincing evidence that PX-478 induces apoptosis by inhibiting the PI3K/AKT/mTOR pathway through downregulation of GBE1 in AML cells.收起

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