2Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, Shandong, China1School of Clinical Medicine, Shandong Second Medical University, Weifang 261000, Shandong, China3Central Hospital Affiliated to Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250013, Shandong, China
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
