Rita A. Avelar, Riya Gupta, Grace Carvette, Felipe da Veiga Leprevost, Medhasri Jasti, Jose Colina, Jessica Teitel, Alexey I. Nesvizhskii, Caitlin M. O’Connor, Maria Hatzoglou, Shirish Shenolikar, Peter Arvan, Goutham Narla, Analisa DiFeo
{"title":"综合应激反应可塑性通过 PP2A-TFE3-ATF4 通路调控正常细胞对慢性应激的适应性","authors":"Rita A. Avelar, Riya Gupta, Grace Carvette, Felipe da Veiga Leprevost, Medhasri Jasti, Jose Colina, Jessica Teitel, Alexey I. Nesvizhskii, Caitlin M. O’Connor, Maria Hatzoglou, Shirish Shenolikar, Peter Arvan, Goutham Narla, Analisa DiFeo","doi":"10.1038/s41418-024-01378-3","DOIUrl":null,"url":null,"abstract":"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.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 12","pages":"1761-1775"},"PeriodicalIF":13.7000,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41418-024-01378-3.pdf","citationCount":"0","resultStr":"{\"title\":\"Integrated stress response plasticity governs normal cell adaptation to chronic stress via the PP2A-TFE3-ATF4 pathway\",\"authors\":\"Rita A. Avelar, Riya Gupta, Grace Carvette, Felipe da Veiga Leprevost, Medhasri Jasti, Jose Colina, Jessica Teitel, Alexey I. Nesvizhskii, Caitlin M. 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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. 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Integrated stress response plasticity governs normal cell adaptation to chronic stress via the PP2A-TFE3-ATF4 pathway
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.
期刊介绍:
Mission, vision and values of Cell Death & Differentiation:
To devote itself to scientific excellence in the field of cell biology, molecular biology, and biochemistry of cell death and disease.
To provide a unified forum for scientists and clinical researchers
It is committed to the rapid publication of high quality original papers relating to these subjects, together with topical, usually solicited, reviews, meeting reports, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.