Pivotal role of the endoplasmic reticulum stress-related XBP1s/miR-22/SIRT1 axis in acute myeloid leukemia apoptosis and response to chemotherapy.

Autor: Philippe C; Barts Cancer Institute, Queen Mary University of London, London, UK. celine.philippe@inserm.fr., Jaud M; Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Féral K; Centre de Recherches en Cancérologie de Toulouse (CRCT), INSERM UMR-1037, CNRS UMR-5071, Université de Toulouse, Toulouse, France., Gay A; Centre de Recherches en Cancérologie de Toulouse (CRCT), INSERM UMR-1037, CNRS UMR-5071, Université de Toulouse, Toulouse, France., Van Den Berghe L; Vectorology Platform, CRCT INSERM UMR-1037 Technological Pole, F-31037, Toulouse, France., Farce M; Flow Cytometry and Cell Sorting Platform, CRCT INSERM UMR-1037 Technological Pole, F-31037, Toulouse, France., Bousquet M; Centre de Recherches en Cancérologie de Toulouse (CRCT), INSERM UMR-1037, CNRS UMR-5071, Université de Toulouse, Toulouse, France., Pyronnet S; Centre de Recherches en Cancérologie de Toulouse (CRCT), INSERM UMR-1037, CNRS UMR-5071, Université de Toulouse, Toulouse, France., Mazzolini L; Centre de Recherches en Cancérologie de Toulouse (CRCT), INSERM UMR-1037, CNRS UMR-5071, Université de Toulouse, Toulouse, France., Rouault-Pierre K; Barts Cancer Institute, Queen Mary University of London, London, UK., Touriol C; Centre de Recherches en Cancérologie de Toulouse (CRCT), INSERM UMR-1037, CNRS UMR-5071, Université de Toulouse, Toulouse, France. christian.touriol@inserm.fr.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2024 Aug; Vol. 38 (8), pp. 1764-1776. Date of Electronic Publication: 2024 Jun 22.
DOI: 10.1038/s41375-024-02321-8
Abstrakt: Malignant growth relies on rapid protein synthesis frequently leading to endoplasmic reticulum (ER) overload and accumulation of unfolded or misfolded protein in this cellular compartment. In the ER, protein homeostasis is finely regulated by a mechanism called the unfolded protein response (UPR), involving the activation of signalization pathways mediated by three transmembrane proteins, namely PERK, IRE1 and ATF6. IRE1 endoribonuclease activation leads in particular to the splicing of the cytosolic mRNA encoding the key UPR-specific transcription factor XBP1s. Our study shows that sustained activation of XBP1s expression in acute myeloid leukemia (AML) cells induces apoptosis in vitro and in vivo, whereas a moderate XBP1s expression sensitizes cells to chemotherapeutic treatments. ChIP-seq experiments identified specific XBP1s target genes including the MIR22HG lncRNA, the precursor transcript of microRNA-22-3p. miR-22-3p upregulation by XBP1s or forced expression of miR-22 significantly decreases cell's viability and sensitizes leukemic cells to chemotherapy. We found that miR-22-3p intracellular effects result at least partially from the targeting of the mRNA encoding the deacetylase sirtuin-1 (SIRT1), a well-established pro-survival factor. Therefore, this novel XBP1s/miR-22/SIRT1 axis identified could play a pivotal role in the proliferation and chemotherapeutic response of leukemic cells.
(© 2024. The Author(s).)
Databáze: MEDLINE
Externí odkaz: