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Cited by 10Extracellular vesicles in diseaseCellular transport and secretionCaveolin-1 and cellular processes

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

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Das Gupta, Anasuya, Park, Jaena, Sorrells, Janet E, Kim, Hannah, Krawczynska, Natalia, Pradeep, Dhanya, Wang, Yu, Vidana Gamage, Hashni Epa +4 more·2024·Endocrinology
DOI 10.1210/endocr/bqae127PMC PMC11448339
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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.

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  • 27-hydroxycholesterol works through liver x receptors in myeloid immune cells to suppress T cell proliferation and function, stimulate secretion of pro-tumor extracellular vesicles, and promote tumor and metastatic growth.

    “An oxysterol metabolite of cholesterol, 27-hydroxycholesterol, was found to work through the liver x receptors in myeloid immune cells to robustly suppress T cell proliferation and function, and stimulate the secretion of pro-tumor extracellular vesicles, ultimately promoting the growth of tumors and metastatic lesions (17, 20–23).”

    From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [21]

    The introductory passage reports that 27HC acts through liver X receptors in myeloid cells to suppress T-cell expansion, and the Discussion reports that 27HC-induced extracellular vesicles promote tumor growth and metastasis. But the paper attributes increased vesicle secretion to mitochondrial dysfunction, oxidative stress, and altered lysosomal function; it does not establish liver X receptors as the mechanism for that secretion or the resulting tumor growth. (LLM, conf=0.86)

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Authors
Das Gupta, A., Park, J., Sorrells, J. E., Kim, H., Krawczynska, N., Pradeep, D., Wang, Y., Vidana Gamage, H. E., Nelczyk, A. T., Boppart, S. A., Boppart, M. D., & Nelson, E. R.
Affiliations
  • Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign , Urbana, IL 61801 ,
  • University of Illinois Urbana-Champaign (US)
Corresponding author
Nelson, Erik R
ORCID
Venue
Endocrinology
Publisher
The Endocrine Society
Published
2024-09-19
Volume
165
Issue
11
ISSN
  • 0013-7227 (ISSN-L)
  • 1945-7170
DOI
10.1210/endocr/bqae127
PMC
PMC11448339
OpenAlex
W4402624164
Cited by
10
References
3
Citations by year
2026: 6 · 2025: 4
FWCI
1.36
Type
journal article
Language
en
Open access
Licence
academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations
  • Endocrinology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion)
Funders
  • National Institutes of Health
  • National Cancer Institute (R01CA234025)
  • National Institute of General Medical Sciences (T32GM136629)
  • National Institute of Environmental Health Sciences (T32ES007326)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR072735)
  • National Institute of Biomedical Imaging and Bioengineering (P41EB031772)
  • Beckman Institute for Advanced Science and Technology, University of Illinois, Urbana-Champaign
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Caveolin-1 and cellular processes
Keywords
27-hydroxycholesterol, extracellular vesicles, EV secretion, lysosomal dysfunction, reactive oxygen species, multivesicular bodies, mitochondrial dysfunction, cholesterol metabolites, myeloid cells, mitochondria-targeted antioxidants, tumor progression, cell-to-cell communication
MeSH terms
Extracellular Vesicles, RAW 264.7 Cells, Animals, Cell Line, Hydroxycholesterols, Lysosomes, Mitochondria, Reactive Oxygen Species, Mice

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Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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