2. Academic Validation
  3. PX-478 induces apoptosis in acute myeloid leukemia under hypoxia by inhibiting the PI3K/AKT/mTOR pathway through downregulation of GBE1

PX-478 induces apoptosis in acute myeloid leukemia under hypoxia by inhibiting the PI3K/AKT/mTOR pathway through downregulation of GBE1

  • Biochem Pharmacol. 2024 Dec;230(Pt 3):116620. doi: 10.1016/j.bcp.2024.116620.
Wenjing Liu 1,  Chunhui Dou 2,  Ce Zhang 3,  Ping Chen 2,  Shu Zhang 1,  Renxiang Wang 3,  Qing Han 1,  Hongyu Zhao 4,  Daqi Li 5
Affiliations

Affiliations

  • 1 School of Clinical Medicine, Shandong Second Medical University, Weifang 261000, Shandong, China.
  • 2 Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, Shandong, China.
  • 3 Central Hospital Affiliated to Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250013, Shandong, China.
  • 4 Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, Shandong, China. Electronic address: zhy_1009@163.com.
  • 5 Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, Shandong, China. Electronic address: ldq1684@zxyy.cn.
PMID: 39528073 DOI: 10.1016/j.bcp.2024.116620
Abstract

Acute myeloid leukemia (AML) 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 (HIF-1α), 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 (GBE1) may be involved in PX-478-induced Apoptosis in AML cells. We found that inhibiting GBE1 expression in AML cells (siGBE1) led to downregulation of the PI3K/Akt/mTOR pathway and induced Apoptosis. In experiments using AML cells with reduced GBE1 expression (shGBE1), 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.

Keywords

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

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