Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with poor prognosis. Insights into the roles of MicroRNAs (miRNAs) in diseases, particularly in cancer, have made miRNAs attractive tools and targets for novel therapeutic approaches. Here, we employed a novel chimeric peptide supramolecular nanoparticle delivery system for plectin-1 (PL-1)-targeted PDAC-specific miR-9 delivery and in pancreatic cancer patient-derived xenograft (PDX) model. RT-PCR and immunohistochemistry (IHC) were conducted to detect the expression pattern of eIF5A2. mRFP-GFP-LC3 fluorescence microscopy and Western blot were carried out to determine autophagy. Luciferase reporter assays were performed to elucidate the regulatory role of miR-9/eIF5A2 axis. PL-1/miR-9 nanocomplexes dramatically improve the anticancer effect of doxorubicin through downregulating eIF5A2 expression to inhibit autophagy and induce apoptosis in PDAC therapy . Mechanistically, miR-9 directly targets the transcript by binding to its 3'-untranslated region (3'-UTR) to reduce the expression levels and the secreted protein of eIF5A2 in PDAC cells. PL-1/miR-9 nanoparticles can be used as a novel promising anti-cancer strategy with tumor targeting and miR-9/eIF5A2 may serve as a new potential therapeutic target for future synergic therapy against human PDAC.
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http://dx.doi.org/10.7150/thno.38327 | DOI Listing |
Front Mol Biosci
December 2024
Department of Chemistry, Western Washington University, Bellingham, WA, United States.
Cellular signaling networks are modulated by multiple protein-protein interaction domains that coordinate extracellular inputs and processes to regulate cellular processes. Several of these domains recognize short linear motifs, or SLiMs, which are often highly conserved and are closely regulated. One such domain, the Src homology 3 (SH3) domain, typically recognizes proline-rich SLiMs and is one of the most abundant SLiM-binding domains in the human proteome.
View Article and Find Full Text PDFCell Commun Signal
December 2024
Inserm UMR 1307, CNRS UMR 6075, Nantes Université, Université d'Angers, CRCI2NA, 44000, Nantes, France.
Background: Ewing sarcoma (ES), the second main pediatric bone sarcoma, is characterised by a chromosomal translocation leading to the formation of fusion proteins like EWS::FLI1. While several studies have shown that potassium channels drive the development of many tumours, limited data exist on ES. This work therefore aimed to study the transcriptional regulation of KCNA2 and define the involvement of the Kv1.
View Article and Find Full Text PDFInt J Mol Sci
December 2024
School of Medicine, Huaqiao University, Quanzhou 362021, China.
Understanding the molecular targets of natural products is crucial for elucidating their mechanisms of action, mitigating toxicity, and uncovering potential therapeutic pathways. Icaritin (ICT), a bioactive flavonoid, demonstrates significant anti-tumor activity but lacks defined molecular targets. This study employs an advanced strategy integrating proteolysis targeting chimera (PROTAC) technology with quantitative proteomics to identify ICT's key targets.
View Article and Find Full Text PDFInt J Mol Sci
November 2024
Institute of Psychology and Human Sciences, WSEI Academy, 20-209 Lublin, Poland.
Marine-derived peptides display potent antihypertensive, antioxidant, analgesic and antimicrobial biological effects. Some of them have also been found to have anticancer activity via various mechanisms differing from those of continental organisms. This diversity of properties-together with the peptides' efficacy, which has been confirmed in several in vitro and in vivo studies-make these compounds attractive as functional ingredients in pharmacy, especially in regard to multitarget drugs known as hybrids.
View Article and Find Full Text PDFNat Biotechnol
December 2024
Department of Chemistry, Stanford University, Stanford, CA, USA.
Identifying highly specific T cell receptors (TCRs) or antibodies against epitopic peptides presented by class I major histocompatibility complex (MHC I) proteins remains a bottleneck in the development of targeted therapeutics. Here, we introduce targeted recognition of antigen-MHC complex reporter for MHC I (TRACeR-I), a generalizable platform for targeting peptides on polymorphic HLA-A*, HLA-B* and HLA-C* allotypes while overcoming the cross-reactivity challenges of TCRs. Our TRACeR-MHC I co-crystal structure reveals a unique antigen recognition mechanism, with TRACeR forming extensive contacts across the entire peptide length to confer single-residue specificity at the accessible positions.
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