Nucleolin perturbation alters membrane lipid homeostasis
AS1411 is a G-rich DNA aptamer that targets the multifunctional RNA-binding protein nucleolin. AS1411 has both antiproliferative and cell size-regulating activities and has been evaluated for clinical utility, reaching phase II trials as an anticancer agent. The mechanisms underlying cell size effects of AS1411 are not well understood and broad characterization of its molecular effects is lacking. Here, we used a multi-omics approach to profile transcriptome, proteome and lipidome changes in AS1411-treated NIH-3T3 cells, which increase in size in response to the aptamer. We found that AS1411 caused downregulation of cholesterol biosynthesis pathway enzymes at both mRNA and protein levels, without an accompanying reduction in cellular cholesterol levels or cholesterol uptake. In addition, AS1411 induced changes in several lipid classes, including increases in phosphatidylethanolamine levels. Ratiometric imaging of Di-4-ANEPPS-labeled cells showed that AS1411 decreases the fluidity of intracellular membranes. Thus, aptamer engagement of nucleolin affects lipid biosynthesis and homeostasis, likely contributing to its roles in cell size control.
Authors
- Ida Rishal (ORCID: https://orcid.org/0000-0002-8778-1369)
- Eitan Erez Zahavi (ORCID: https://orcid.org/0000-0002-9555-2654)
- Šárka Pokorná (ORCID: https://orcid.org/0000-0002-7046-9440)
- Sergey Malitsky (ORCID: https://orcid.org/0000-0003-4619-7219)
- Alexander Brandis (ORCID: https://orcid.org/0000-0001-9604-2229)
- Anthony H. Futerman (ORCID: https://orcid.org/0000-0003-0013-0115)
- Florencia Cabrera-Cabrera (ORCID: https://orcid.org/0000-0003-0324-2542)
- Natjan-Naatan Seeba (ORCID: https://orcid.org/0000-0003-2044-8710)
- Aivar Lõokene (ORCID: https://orcid.org/0000-0002-0157-727X)
- Mike Fainzilber (ORCID: https://orcid.org/0000-0001-8173-8557)
- Indrek Koppel (ORCID: https://orcid.org/0000-0002-9338-8889)
- Maxim Itkin (ORCID: https://orcid.org/0000-0003-1348-2814)
- Robert Risti (ORCID: https://orcid.org/0000-0001-5623-8235)
- Juan A. Osés-Prieto (ORCID: https://orcid.org/0000-0003-4759-2341)
- Alma L. Burlingame
Institutions
- Tallinn University of Technology (EE)
- University of California, San Francisco (US)
- Weizmann Institute of Science (IL)
Publication Details
- Journal
- Molecular Omics
- Published
- 2025-10-28
- DOI
- https://doi.org/10.1039/d5mo00088b
- Primary Topic
- Nuclear Structure and Function
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Eesti Teadusagentuur
- National Institutes of Health
- Institute for Advanced Studies in the Humanities, University of Edinburgh
- National Institute of General Medical Sciences