J Leukoc Biol. 2025 May 16:qiaf065. doi: 10.1093/jleuko/qiaf065. Online ahead of print.
ABSTRACT
Hypoxia-associated H2S accumulation promotes chemotherapy resistance in solid tumor cells. This study delved into the mechanism by which CBS/H2S signaling is involved in the development of acute myeloid leukemia (AML) resistance to cytarabine (ara-C) under hypoxic conditions. The levels of CBS and H2S in AML cells and ara-c-resistant AML cells were evaluated. Subsequently, the expression of CBS and H2S under normoxic and hypoxic conditions in ara-c-resistant AML cells were further scrutinized. Sh-CBS or sh-THBS1 was transfected into ara-c-resistant AML cells, which were then exposed to 1% oxygen and/or ara-C. The cell viability, apoptosis, lipid metabolism level were evaluated by CCK-8, flow cytometry, kit and qPCR. Simultaneously, the methylation of THBS1 was detected via methylation-specific PCR analysis. The expression of CBS and H2S is elevated in ara-C-resistant AML cells, rising proportionally with diminishing oxygen concentration. In ara-C-resistant AML cells, hypoxia stimulated cell viability, suppressed apoptosis, augmented total cholesterol and triacylglycerol levels, upregulated the levels of CD36 and CPT1α as well as downregulated SCAD and PPARα levels, while these effects of hypoxia were all reversed by sh-CBS. Sh-CBS notably decreases the hypermethylation level of THBS1 in ara-C-resistant AML cells. Sh-THBS1 reversed the regulatory effect of sh-CBS on lipid metabolism, cell viability, and apoptosis in ara-C-resistant AML cells. Conversely, sh-CD36 effectively overrode the reversal impact of sh-THBS1. Activation of CBS/H2S signaling in a hypoxic environment participates in the ara-C resistance of AML cells by facilitating CD36-mediated fatty acid metabolism through mediation of THBS1 methylation.
PMID:40376852 | DOI:10.1093/jleuko/qiaf065