27-Hydroxycholesterol Enhances Secretion of Extracellular Vesicles by ROS-Induced Dysregulation of Lysosomes

Abstract Extracellular vesicles (EVs) serve as crucial mediators of cell-to-cell communication in normal physiology as well as in diseased states; they have been largely studied in regard to their role in cancer progression. However, the mechanisms by which their biogenesis and secretion are regulat...

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Published in:Endocrinology (Philadelphia) 2024-09, Vol.165 (11)
Main Authors: Das Gupta, Anasuya, Park, Jaena, Sorrells, Janet E, Kim, Hannah, Krawczynska, Natalia, Pradeep, Dhanya, Wang, Yu, Vidana Gamage, Hashni Epa, Nelczyk, Adam T, Boppart, Stephen A, Boppart, Marni D, Nelson, Erik R
Format: Article
Language:English
Subjects:
Cancer
Cell interactions
Cholesterol
Development strategies
Extracellular vesicles
Homeostasis
Immune system
Lysosomes
Metabolites
Reactive oxygen species
Vesicles
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Summary:Abstract Extracellular vesicles (EVs) serve as crucial mediators of cell-to-cell communication in normal physiology as well as in diseased states; they have been largely studied in regard to their role in cancer progression. However, the mechanisms by which their biogenesis and secretion are regulated by metabolic or endocrine factors remain unknown. Here, we delineate a mechanism by which EV secretion is regulated by a cholesterol metabolite, 27-hydroxycholesterol (27HC), where treatment of myeloid immune cells (RAW 264.7 and J774A.1) with 27HC impairs lysosomal homeostasis, leading to shunting of multivesicular bodies (MVBs) away from lysosomal degradation, toward secretion as EVs. This altered lysosomal function is likely caused by mitochondrial dysfunction and subsequent increase in reactive oxygen species (ROS). Interestingly, cotreatment with a mitochondria-targeted antioxidant rescued the lysosomal impairment and attenuated the 27HC-mediated increase in EV secretion. Overall, our findings establish how a cholesterol metabolite regulates EV secretion and paves the way for the development of strategies to regulate cancer progression by controlling EV secretion.
ISSN:1945-7170
0013-7227
1945-7170
DOI:10.1210/endocr/bqae127