p66ShcA promotes malignant breast cancer phenotypes by alleviating energetic and oxidative stress.

Autor:	Lewis K; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada; Department of Biochemistry, McGill University, Montreal, QC, Canada., La Selva R; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada; Division of Experimental Medicine, McGill University, Montreal, QC, Canada., Maldonado E; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada; Division of Experimental Medicine, McGill University, Montreal, QC, Canada., Annis MG; Goodman Cancer Institute, McGill University, Montreal, QC, Canada., Najyb O; Department of Biochemistry, McGill University, Montreal, QC, Canada; Goodman Cancer Institute, McGill University, Montreal, QC, Canada., Cepeda Cañedo E; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada; Division of Experimental Medicine, McGill University, Montreal, QC, Canada., Totten S; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada; Division of Experimental Medicine, McGill University, Montreal, QC, Canada., Hébert S; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada., Sabourin V; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada., Mirabelli C; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada; Division of Experimental Medicine, McGill University, Montreal, QC, Canada., Ciccolini E; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada; Division of Experimental Medicine, McGill University, Montreal, QC, Canada., Lehuédé C; Goodman Cancer Institute, McGill University, Montreal, QC, Canada., Choinière L; Goodman Cancer Institute, McGill University, Montreal, QC, Canada., Russo M; Goodman Cancer Institute, McGill University, Montreal, QC, Canada., Avizonis D; Goodman Cancer Institute, McGill University, Montreal, QC, Canada., Park M; Department of Biochemistry, McGill University, Montreal, QC, Canada; Division of Experimental Medicine, McGill University, Montreal, QC, Canada; Goodman Cancer Institute, McGill University, Montreal, QC, Canada; Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, Canada., St-Pierre J; Department of Biochemistry, Microbiology and Immunology and Ottawa Institute of Systems Biology, University of Ottawa, ON, Canada., Kleinman CL; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada; Department of Human Genetics, McGill University, Montreal, QC, Canada., Siegel PM; Department of Biochemistry, McGill University, Montreal, QC, Canada; Division of Experimental Medicine, McGill University, Montreal, QC, Canada; Goodman Cancer Institute, McGill University, Montreal, QC, Canada; Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, Canada., Ursini-Siegel J; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada; Department of Biochemistry, McGill University, Montreal, QC, Canada; Division of Experimental Medicine, McGill University, Montreal, QC, Canada; Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, Canada. Electronic address: giuseppina.ursini-siegel@mcgill.ca.
Jazyk:	angličtina
Zdroj:	Redox biology [Redox Biol] 2024 Apr; Vol. 70, pp. 103028. Date of Electronic Publication: 2024 Jan 05.
DOI:	10.1016/j.redox.2024.103028
Abstrakt:	Significant efforts have focused on identifying targetable genetic drivers that support the growth of solid tumors and/or increase metastatic ability. During tumor development and progression to metastatic disease, physiological and pharmacological selective pressures influence parallel adaptive strategies within cancer cell sub-populations. Such adaptations allow cancer cells to withstand these stressful microenvironments. This Darwinian model of stress adaptation often prevents durable clinical responses and influences the emergence of aggressive cancers with increased metastatic fitness. However, the mechanisms contributing to such adaptive stress responses are poorly understood. We now demonstrate that the p66ShcA redox protein, itself a ROS inducer, is essential for survival in response to physiological stressors, including anchorage independence and nutrient deprivation, in the context of poor outcome breast cancers. Mechanistically, we show that p66ShcA promotes both glucose and glutamine metabolic reprogramming in breast cancer cells, to increase their capacity to engage catabolic metabolism and support glutathione synthesis. In doing so, chronic p66ShcA exposure contributes to adaptive stress responses, providing breast cancer cells with sufficient ATP and redox balance needed to withstand such transient stressed states. Our studies demonstrate that p66ShcA functionally contributes to the maintenance of aggressive phenotypes and the emergence of metastatic disease by forcing breast tumors to adapt to chronic and moderately elevated levels of oxidative stress. Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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