ArticleNaunyn-Schmiedeberg's archives of pharmacology2026
METTL3/IGF2BP3 axis promotes gemcitabine resistance of pancreatic cancer cells through regulating USP33-mediated PAK1 deubiquitination and degradation.
Article in Naunyn-Schmiedeberg's archives of pharmacology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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Who cites it
1 citing paper in PubMed.
- USP33 Promotes Lung Adenocarcinoma Brain Metastasis by Inhibiting the K48-Linked Ubiquitination and Degradation of S100A9 and Facilitating Vimentin Secretion.International journal of biological sciences · 2026Article
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5 authors.
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Abstract
Although gemcitabine (GEM) is the standard of care for most patients with pancreatic cancer (PC), its efficacy is limited by resistance development. Furthermore, p21-activated kinase-1 (PAK1) has been demonstrated to be involved in regulating the development of PC with GEM resistance. This study is designed to explore the role and mechanism of PAK1 in the GEM resistance of PC cells. PAK1, ubiquitin-specific peptidase 33 (USP33), methyltransferase-like 3 (METTL3), and insulin-like growth factor-2 mRNA-binding protein 3 (IGF2BP3) mRNA levels were detected using RT-qPCR. PAK1, MDR1, MRP1, USP33, METTL3, and IGF2BP3 protein levels were examined by western blot. GEM resistance, cell viability, proliferation, apoptosis, invasion, and migration were assessed using MTT, EdU, flow cytometry, transwell, and wound healing assays. After ubibrowser database analysis, the interaction between USP33 and PAK1 was verified using co-immunoprecipitation (Co-IP) assay. Meanwhile, the interaction between METTL3 and USP33 m6A was analyzed using methylated RNA immunoprecipitation (MeRIP)-qPCR and RNA immunoprecipitation (RIP) assay. A xenograft model analyzed the effects of PAK1 on GEM resistance of PC in vivo. PAK1 was upregulated in GEM-resistant PC tissues and cells. PAK1 knockdown enhanced cell sensitivity to GEM; repressed cell proliferation, invasion, and migration; and induced cell apoptosis in vitro. Mechanistically, USP33 triggered the deubiquitination of PAK1 and prevented its degradation. METTL3 stabilized USP33 mRNA through the m6A-IGF2BP3-dependent mechanism and naturally increased USP33 expression. USP33 silencing increased the drug sensitivity of PC in vivo. METTL3 supports GEM resistance of PC cells partly by regulating USP33-mediated PAK1 deubiquitination, providing a promising therapeutic target for GEM-resistant PC cells.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.