bims-hypusi 2023-03-12 papers

Issue of 2023–03–12
two papers selected by
Sebastian J. Hofer, University of Graz

Acta Cir Bras. 2023 ;pii: S0102-86502023000100201. [Epub ahead of print]38 e380323

Circular RNA protein tyrosine kinase 2 aggravates pyroptosis and inflammation in septic lung tissue by promoting microRNA-766/eukaryotic initiation factor 5A axis-mediated ATP efflux.

FuYan Ding, JiaLu Zhu, YanLei Hu.

PURPOSE: Sepsis is characterized by an acute inflammatory response to infection, often with multiple organ failures, especially severe lung injury. This study was implemented to probe circular RNA (circRNA) protein tyrosine kinase 2 (circPTK2)-associated regulatory mechanisms in septic acute lung injury (ALI).
METHODS: A cecal ligation and puncture-based mouse model and an lipopolysaccharides (LPS)-based alveolar type II cell (RLE-6TN) model were generated to mimic sepsis. In the two models, inflammation- and pyroptosis-related genes were measured.
RESULTS: The degree of lung injury in mice was analyzed by hematoxylin and eosin (H&E) staining and the apoptosis was by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling staining. In addition, pyroptosis and toxicity were detected in cells. Finally, the binding relationship between circPTK2, miR-766, and eukaryotic initiation factor 5A (eIF5A) was detected. Data indicated that circPTK2 and eIF5A were up-regulated and miR-766 was down-regulated in LPS-treated RLE-6TN cells and lung tissue of septic mice. Lung injury in septic mice was ameliorated after inhibition of circPTK2.
CONCLUSIONS: It was confirmed in the cell model that knockdown of circPTK2 effectively ameliorated LPS-induced ATP efflux, pyroptosis, and inflammation. Mechanistically, circPTK2 mediated eIF5A expression by competitively adsorbing miR-766. Taken together, circPTK2/miR-766/eIF5A axis ameliorates septic ALI, developing a novel therapeutic target for the disease.

DOI: https://doi.org/10.1590/acb380323

Cancer Lett. 2023 Mar 07. pii: S0304-3835(23)00071-X. [Epub ahead of print] 216120

Combined inhibition of polyamine metabolism and eIF5A hypusination suppresses colorectal cancer growth through a converging effect on MYC translation.

Sonia Coni, Rosa Bordone, Devon Michael Ivy, Zuleyha Nihan Yurtsever, Laura Di Magno, Rodrigo D'Amico, Bianca Cesaro, Alessandro Fatica, Francesca Belardinilli, Francesca Bufalieri, Marella Maroder, Enrico De Smaele, Lucia Di Marcotullio, Giuseppe Giannini, Enzo Agostinelli, Gianluca Canettieri.

A key mechanism driving colorectal cancer (CRC) development is the upregulation of MYC and its targets, including ornithine decarboxylase (ODC), a master regulator of polyamine metabolism. Elevated polyamines promote tumorigenesis in part by activating DHPS-mediated hypusination of the translation factor eIF5A, thereby inducing MYC biosynthesis. Thus, MYC, ODC and eIF5A orchestrate a positive feedback loop that represents an attractive therapeutic target for CRC therapy. Here we show that combined inhibition of ODC and eIF5A induces a synergistic antitumor response in CRC cells, leading to MYC suppression. We found that genes of the polyamine biosynthesis and hypusination pathways are significantly upregulated in colorectal cancer patients and that inhibition of ODC or DHPS alone limits CRC cell proliferation through a cytostatic mechanism, while combined ODC and DHPS/eIF5A blockade induces a synergistic inhibition, accompanied to apoptotic cell death in vitro and in mouse models of CRC and FAP. Mechanistically, we found that this dual treatment causes complete inhibition of MYC biosynthesis in a bimodal fashion, by preventing translational elongation and initiation. Together, these data illustrate a novel strategy for CRC treatment, based on the combined suppression of ODC and eIF5A, which holds promise for the treatment of CRC.

Keywords: DFMO; GC7; Mouse models; Polyamines; Synergy

DOI: https://doi.org/10.1016/j.canlet.2023.216120