ArticleCell biology and toxicology2024
RNF38 promotes gilteritinib resistance in acute myeloid leukemia via inducing autophagy by regulating ubiquitination of LMX1A.
Article in Cell biology and toxicology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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3 citing papers in PubMed.
- Tongguanteng Injection Induces Apoptosis of Colorectal Cancer Cells Via Inhibiting PTGS2 Mediated PD-L1 Checkpoint Pathway: Insights from Network Pharmacology and Experimental Validation.Applied biochemistry and biotechnology · 2026Article
- The Memory Gene,Biomolecules · 2025Article
- The ubiquitination-autophagy axis in cancer therapy resistance: mechanistic insights and therapeutic opportunities.Frontiers in pharmacology · 2025Review
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Abstract
backgroundGilteritinib is a commonly used targeted drug for acute myeloid leukemia (AML), but the emergence of gilteritinib resistance greatly reduces the therapeutic effect. RING finger protein 38 (RNF38), a protein with RING Finger domain and E3 ubiquitin ligase activity, has been implicated in tumorigenesis and drug resistance. However, the role and mechanism of RNF38 in the gilteritinib resistance of AML remains unclear.
methodsNormal AML cells were treated with gilteritinib to construct gilteritinib-resistant cells (MV4-11/Gilteritinib and MOLM-13/Gilteritinib). CCK8 assay, TUNEL staining and EdU assay were used to assess gilteritinib resistance, cell apoptosis and proliferation. The protein levels of autophagy-related markers, RNF38 and LIM homeobox transcription factor 1 alpha (LMX1A) were determined by western blot. Also, RNF38 and LMX1A mRNA levels were tested using qRT-PCR. Autophagic flux was assessed using mRFP-GFP-LC3 labeling, and autophagosome numbers was counted under transmission electron microscopy. Co-IP assay was employed to analyze interaction between RNF38 and LMX1A. The effects of LMX1A and RNF38 on AML tumorigenesis were analyzed by in vivo experiments.
resultsIn gilteritinib-resistant AML cells, autophagy-related markers, mRFP-GFP-LC3 signals and autophagosome numbers were significantly enhanced. Autophagy inhibitor 3-MA could suppress gilteritinib resistance in AML cells. RNF38 knockdown inhibited gilteritinib resistance and autophagy in AML cells. Mechanistically, RNF38 reduced LMX1A expression by inducing its ubiquitination. RNF38 overexpression reversed the inhibitory effect of LMX1A on gilteritinib resistance and autophagy in AML cells, as well as AML tumor growth in vivo, while these effects could be abolished by proteasome inhibitor MG132.
conclusionsRNF38 induced autophagy to promote gilteritinib resistance in AML by increasing the ubiquitination of LMX1A.
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