Archives of medical science : AMS · 2025
UBC9 silencing-mediated PPARα deSUMOylation induces inhibition of cell proliferation by ferroptosis in acute myeloid leukemia.
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Du Li, Zhang Jinrong, Zhang Xiyue, Li Chunyan, Wang Qi, Meng Guangping, Kan Xingchi, Zhang Jie, Jia Yuxi
Аннотация
INTRODUCTION: Inhibited acute myeloid leukemia (AML) proliferation is accompanied by downregulated peroxisome proliferator-activated receptor α (PPARα), which however can be stabilized via SUMOylation. This study investigated how PPARα SUMOylation impacts AML cell growth.
MATERIAL AND METHODS: Human AML HL-60 and Tohoku Hospital Pediatrics-1 (THP-1) cells were treated with the PPARα inhibitor GW6471 (10 µM) for 24 and 48 h. THP-1 cells were exposed to the PPARα agonist pirinixic acid (10 µM) following manipulation of the expression of the small ubiquitin-like modifier protein (SUMO)-conjugating enzyme UBC9. The interaction between PPARα and SUMO1 was detected by immunoprecipitation assay. HL-60 and THP-1 cell viability, apoptosis, and ferroptosis were measured via Cell Counting Kit-8 assay, flow cytometry, BODIPY-C11 staining and/or colorimetric assay. UBC9, glutathione peroxidase 4 (GPX4), recombinant solute carrier family 7, member 11(SLC7A11) and PPARα expression levels were analyzed by qRT-PCR or Western blot.
RESULTS: GW6471 treatment for 24 and 48 h suppressed viability, promoted apoptosis and lipid peroxidation, increased the level of Fe2+, and decreased the expression of GPX4, SLC7A11 and PPARα in HL-60/THP-1 cells. PPARα antibody induced enrichment of PPARα and SUMO1 in THP-1 cells, which was attenuated after UBC9 silencing. UBC9 silencing resulted in viability decrease, apoptosis and lipid peroxidation promotion, Fe2+ upregulation, and GPX4, SLC7A11, and PPARα downregulation in THP-1 cells, which were all counteracted by pirinixic acid.
CONCLUSIONS: UBC9 silencing-induced PPARα deSUMOylation induces suppression of AML cell growth by ferroptosis.
MATERIAL AND METHODS: Human AML HL-60 and Tohoku Hospital Pediatrics-1 (THP-1) cells were treated with the PPARα inhibitor GW6471 (10 µM) for 24 and 48 h. THP-1 cells were exposed to the PPARα agonist pirinixic acid (10 µM) following manipulation of the expression of the small ubiquitin-like modifier protein (SUMO)-conjugating enzyme UBC9. The interaction between PPARα and SUMO1 was detected by immunoprecipitation assay. HL-60 and THP-1 cell viability, apoptosis, and ferroptosis were measured via Cell Counting Kit-8 assay, flow cytometry, BODIPY-C11 staining and/or colorimetric assay. UBC9, glutathione peroxidase 4 (GPX4), recombinant solute carrier family 7, member 11(SLC7A11) and PPARα expression levels were analyzed by qRT-PCR or Western blot.
RESULTS: GW6471 treatment for 24 and 48 h suppressed viability, promoted apoptosis and lipid peroxidation, increased the level of Fe2+, and decreased the expression of GPX4, SLC7A11 and PPARα in HL-60/THP-1 cells. PPARα antibody induced enrichment of PPARα and SUMO1 in THP-1 cells, which was attenuated after UBC9 silencing. UBC9 silencing resulted in viability decrease, apoptosis and lipid peroxidation promotion, Fe2+ upregulation, and GPX4, SLC7A11, and PPARα downregulation in THP-1 cells, which were all counteracted by pirinixic acid.
CONCLUSIONS: UBC9 silencing-induced PPARα deSUMOylation induces suppression of AML cell growth by ferroptosis.