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© 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Platinum (Pt)-based chemotherapy is the main treatment for ovarian cancer (OC); however, most patients develop Pt resistance (Pt-R). This work shows that Pt-R OC cells increase intracellular cholesterol through uptake via the HDL receptor, scavenger receptor type B-1 (SR-B1). SR-B1 blockade using synthetic cholesterol-poor HDL-like nanoparticles (HDL NPs) diminished cholesterol uptake leading to cell death and inhibition of tumor growth. Reduced cholesterol accumulation in cancer cells induces lipid oxidative stress through the reduction of glutathione peroxidase 4 (GPx4) leading to ferroptosis. In turn, GPx4 depletion induces decreased cholesterol uptake through SR-B1 and re-sensitizes OC cells to Pt. Mechanistically, GPx4 knockdown causes lower expression of the histone acetyltransferase EP300, leading to reduced deposition of histone H3 lysine 27 acetylation (H3K27Ac) on the sterol regulatory element binding transcription factor 2 (SREBF2) promoter and suppressing expression of this key transcription factor involved in the regulation of cholesterol metabolism. SREBF2 downregulation leads to decreased SR-B1 expression and diminished cholesterol uptake. Thus, chemoresistance and cancer cell survival under high ROS burden obligates high GPx4 and SR-B1 expression through SREBF2. Targeting SR-B1 to modulate cholesterol uptake inhibits this axis and causes ferroptosis in vitro and in vivo in Pt-R OC.

Details

Title
Nanoparticle Targeting in Chemo-Resistant Ovarian Cancer Reveals Dual Axis of Therapeutic Vulnerability Involving Cholesterol Uptake and Cell Redox Balance
Author
Wang, Yinu 1   VIAFID ORCID Logo  ; Calvert, Andrea E 2 ; Cardenas, Horacio 1 ; Rink, Jonathon S 3 ; Nahotko, Dominik 3 ; Wenan Qiang 4 ; Ndukwe, C Estelle 1 ; Chen, Fukai 5 ; Keathley, Russell 1 ; Zhang, Yaqi 1 ; Ji-Xin, Cheng 5 ; C. Shad Thaxton 6 ; Matei, Daniela 7   VIAFID ORCID Logo 

 Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA 
 Simpson Querrey Institute for BioNanotechnology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA 
 Division of Hematology/ Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA 
 Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; Center for Developmental Therapeutics,Feinberg School of Medicine, Northwestern University, Evanston, IL, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA 
 Department of Physics, Boston University, Boston, MA, USA 
 Simpson Querrey Institute for BioNanotechnology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA; Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA 
 Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA; Jesse Brown Veteran Affairs Medical Center, Chicago, IL, USA 
Section
Research Articles
Publication year
2024
Publication date
Apr 2024
Publisher
John Wiley & Sons, Inc.
e-ISSN
21983844
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3030880270
Copyright
© 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.