Nanoparticle Targeting in Chemo-Resistant Ovarian Cancer Reveals Dual Axis of Therapeutic Vulnerability Involving Cholesterol Uptake and Cell Redox Balance

Yinu Wang; Andrea E. Calvert; Horacio Cardenas; Jonathon S. Rink; Dominik Nahotko; Wenan Qiang; C. Estelle Ndukwe; Fukai Chen; Russell Keathley; Yaqi Zhang; Ji Xin Cheng; C. Shad Thaxton; Daniela Matei

doi:10.1002/advs.202305212

Nanoparticle Targeting in Chemo-Resistant Ovarian Cancer Reveals Dual Axis of Therapeutic Vulnerability Involving Cholesterol Uptake and Cell Redox Balance

Yinu Wang, Andrea E. Calvert, Horacio Cardenas, Jonathon S. Rink, Dominik Nahotko, Wenan Qiang, C. Estelle Ndukwe, Fukai Chen, Russell Keathley, Yaqi Zhang, Ji Xin Cheng, C. Shad Thaxton^*, Daniela Matei^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

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.

Original language	English (US)
Article number	2305212
Journal	Advanced Science
Volume	11
Issue number	13
DOIs	https://doi.org/10.1002/advs.202305212
State	Published - Apr 3 2024

Funding

This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs, through the Ovarian Cancer Ressearch Program under Award Nos. W81XWH-21-1-0378. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. The authors thank Dr. Mazhar Adli for providing the OVCAR4 Pt-S and Pt-R cells, and Dr. Guangyuan Zhao for GSEA bioinformatic analysis. Flow cytometry analyses were performed in the Northwestern University Flow Cytometry Core Facility supported by the Cancer Center Support Grant NCI CA060553. PDX experiments were performed in the Center for Developmental Therapeutics (CDT) partly supported by Cancer Center Support Grant NCI CA060553. This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs, through the Ovarian Cancer Ressearch Program under Award Nos. W81XWH\u201021\u20101\u20100378. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. The authors thank Dr. Mazhar Adli for providing the OVCAR4 Pt\u2010S and Pt\u2010R cells, and Dr. Guangyuan Zhao for GSEA bioinformatic analysis. Flow cytometry analyses were performed in the Northwestern University Flow Cytometry Core Facility supported by the Cancer Center Support Grant NCI CA060553. PDX experiments were performed in the Center for Developmental Therapeutics (CDT) partly supported by Cancer Center Support Grant NCI CA060553.

Keywords

cholesterol uptake
ferroptosis
platinum resistant ovarian cancer
redox targeting

ASJC Scopus subject areas

Medicine (miscellaneous)
General Chemical Engineering
General Materials Science
Biochemistry, Genetics and Molecular Biology (miscellaneous)
General Engineering
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/advs.202305212

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Wang, Y., Calvert, A. E., Cardenas, H., Rink, J. S., Nahotko, D., Qiang, W., Ndukwe, C. E., Chen, F., Keathley, R., Zhang, Y., Cheng, J. X., Thaxton, C. S., & Matei, D. (2024). Nanoparticle Targeting in Chemo-Resistant Ovarian Cancer Reveals Dual Axis of Therapeutic Vulnerability Involving Cholesterol Uptake and Cell Redox Balance. Advanced Science, 11(13), Article 2305212. https://doi.org/10.1002/advs.202305212

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title = "Nanoparticle Targeting in Chemo-Resistant Ovarian Cancer Reveals Dual Axis of Therapeutic Vulnerability Involving Cholesterol Uptake and Cell Redox Balance",

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.",

keywords = "cholesterol uptake, ferroptosis, platinum resistant ovarian cancer, redox targeting",

author = "Yinu Wang and Calvert, {Andrea E.} and Horacio Cardenas and Rink, {Jonathon S.} and Dominik Nahotko and Wenan Qiang and Ndukwe, {C. Estelle} and Fukai Chen and Russell Keathley and Yaqi Zhang and Cheng, {Ji Xin} and Thaxton, {C. Shad} and Daniela Matei",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors. Advanced Science published by Wiley-VCH GmbH.",

year = "2024",

month = apr,

day = "3",

doi = "10.1002/advs.202305212",

language = "English (US)",

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Wang, Y, Calvert, AE, Cardenas, H, Rink, JS, Nahotko, D, Qiang, W, Ndukwe, CE, Chen, F, Keathley, R, Zhang, Y, Cheng, JX, Thaxton, CS & Matei, D 2024, 'Nanoparticle Targeting in Chemo-Resistant Ovarian Cancer Reveals Dual Axis of Therapeutic Vulnerability Involving Cholesterol Uptake and Cell Redox Balance', Advanced Science, vol. 11, no. 13, 2305212. https://doi.org/10.1002/advs.202305212

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T1 - Nanoparticle Targeting in Chemo-Resistant Ovarian Cancer Reveals Dual Axis of Therapeutic Vulnerability Involving Cholesterol Uptake and Cell Redox Balance

AU - Wang, Yinu

AU - Calvert, Andrea E.

AU - Cardenas, Horacio

AU - Rink, Jonathon S.

AU - Nahotko, Dominik

AU - Qiang, Wenan

AU - Ndukwe, C. Estelle

AU - Chen, Fukai

AU - Keathley, Russell

AU - Zhang, Yaqi

AU - Cheng, Ji Xin

AU - Thaxton, C. Shad

AU - Matei, Daniela

PY - 2024/4/3

Y1 - 2024/4/3

N2 - 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.

AB - 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.

KW - cholesterol uptake

KW - ferroptosis

KW - platinum resistant ovarian cancer

KW - redox targeting

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Nanoparticle Targeting in Chemo-Resistant Ovarian Cancer Reveals Dual Axis of Therapeutic Vulnerability Involving Cholesterol Uptake and Cell Redox Balance

Abstract

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Keywords

ASJC Scopus subject areas

UN SDGs

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