Integrated stress response plasticity governs normal cell adaptation to chronic stress via the PP2A-TFE3-ATF4 pathway.

Autor: A Avelar R; Department of Pathology, The University of Michigan, Ann Arbor, MI, USA.; Rogel Cancer Center, The University of Michigan, Ann Arbor, MI, USA., Gupta R; Department of Pathology, The University of Michigan, Ann Arbor, MI, USA.; Rogel Cancer Center, The University of Michigan, Ann Arbor, MI, USA., Carvette G; Department of Pathology, The University of Michigan, Ann Arbor, MI, USA.; Rogel Cancer Center, The University of Michigan, Ann Arbor, MI, USA., da Veiga Leprevost F; Department of Pathology, The University of Michigan, Ann Arbor, MI, USA., Jasti M; Department of Pathology, The University of Michigan, Ann Arbor, MI, USA.; Rogel Cancer Center, The University of Michigan, Ann Arbor, MI, USA., Colina J; Department of Pathology, The University of Michigan, Ann Arbor, MI, USA.; Rogel Cancer Center, The University of Michigan, Ann Arbor, MI, USA., Teitel J; Department of Pathology, The University of Michigan, Ann Arbor, MI, USA.; Rogel Cancer Center, The University of Michigan, Ann Arbor, MI, USA., Nesvizhskii AI; Department of Pathology, The University of Michigan, Ann Arbor, MI, USA.; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA., O'Connor CM; Rogel Cancer Center, The University of Michigan, Ann Arbor, MI, USA.; Department of Internal Medicine, Division of Genetic Medicine, University of Michigan, Ann Arbor, MI, USA., Hatzoglou M; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA., Shenolikar S; Duke-NUS Medical School, Singapore, Singapore.; Duke University School of Medicine, Durham, NC, USA., Arvan P; Division of Metabolism Endocrinology and Diabetes, University of Michigan Medical Center, Ann Arbor, MI, USA., Narla G; Rogel Cancer Center, The University of Michigan, Ann Arbor, MI, USA.; Department of Internal Medicine, Division of Genetic Medicine, University of Michigan, Ann Arbor, MI, USA., DiFeo A; Department of Pathology, The University of Michigan, Ann Arbor, MI, USA. adifeo@med.umich.edu.; Rogel Cancer Center, The University of Michigan, Ann Arbor, MI, USA. adifeo@med.umich.edu.; Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA. adifeo@med.umich.edu.
Jazyk: angličtina
Zdroj: Cell death and differentiation [Cell Death Differ] 2024 Sep 30. Date of Electronic Publication: 2024 Sep 30.
DOI: 10.1038/s41418-024-01378-3
Abstrakt: The integrated stress response (ISR) regulates cell fate during conditions of stress by leveraging the cell's capacity to endure sustainable and efficient adaptive stress responses. Protein phosphatase 2A (PP2A) activity modulation has been shown to be successful in achieving both therapeutic efficacy and safety across various cancer models. However, the molecular mechanisms driving its selective antitumor effects remain unclear. Here, we show for the first time that ISR plasticity relies on PP2A activation to regulate drug response and dictate cellular survival under conditions of chronic stress. We demonstrate that genetic and chemical modulation of the PP2A leads to chronic proteolytic stress and triggers an ISR to dictate whether the cell lives or dies. More specifically, we uncovered that the PP2A-TFE3-ATF4 pathway governs ISR cell plasticity during endoplasmic reticular and cellular stress independent of the unfolded protein response. We further show that normal cells reprogram their genetic signatures to undergo ISR-mediated adaptation and homeostatic recovery thereby avoiding toxicity following PP2A-mediated stress. Conversely, oncogenic specific cytotoxicity induced by chemical modulation of PP2A is achieved by activating chronic and irreversible ISR in cancer cells. Our findings propose that a differential response to chemical modulation of PP2A is determined by intrinsic ISR plasticity, providing a novel biological vulnerability to selectively induce cancer cell death and improve targeted therapeutic efficacy.
(© 2024. The Author(s).)
Databáze: MEDLINE
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