Sterol-like drugs potentiate statin-triggered prostate cancer cell death by inhibiting SREBP2 nuclear translocation

Diandra Zipinotti Dos Santos; Mohamad Elbaz; Emily Branchard; Wiebke Schormann; Carla E Brown; Autumn R Meek; Vincent C O Njar; Robert J Hamilton; Mark A Reed; David W Andrews; Linda Z Penn

doi:10.1016/j.biopha.2024.116934

Sterol-like drugs potentiate statin-triggered prostate cancer cell death by inhibiting SREBP2 nuclear translocation

Biomed Pharmacother. 2024 Aug:177:116934. doi: 10.1016/j.biopha.2024.116934. Epub 2024 Jun 17.

Authors

Affiliations

¹ Princess Margaret Cancer Centre, University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada.
² Princess Margaret Cancer Centre, University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Helwan University, Ain Helwan, Helwan, Cairo, Egypt.
³ Biological Sciences, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada.
⁴ Krembil Research Institute, 60 Leonard Ave, Toronto, ON M5T 0S8, Canada.
⁵ Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA; The Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA; Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA.
⁶ Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
⁷ Krembil Research Institute, 60 Leonard Ave, Toronto, ON M5T 0S8, Canada; Department of Pharmacology and Toxicology, Medical Sciences Building,1 King's College Circle, University of Toronto, M5S 1A8, Canada; Department of Chemistry, Lash Miller Building, 80 St. George Street, University of Toronto, Ontario M5S 3H6, Canada.
⁸ Biological Sciences, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada; Department of Biochemistry, University of Toronto, 27 King's College Cir, Toronto, ON M5S 1A1, Canada; Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada.
⁹ Princess Margaret Cancer Centre, University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada. Electronic address: Linda.Penn@uhnresearch.ca.

PMID: 38889639
DOI: 10.1016/j.biopha.2024.116934

Abstract

There is an urgent need to provide immediate and effective options for the treatment of prostate cancer (PCa) to prevent progression to lethal castration-resistant PCa (CRPC). The mevalonate (MVA) pathway is dysregulated in PCa, and statin drugs commonly prescribed for hypercholesterolemia, effectively target this pathway. Statins exhibit anti-PCa activity, however the resulting intracellular depletion of cholesterol triggers a feedback loop that restores MVA pathway activity, thus diminishing statin efficacy and contributing to resistance. To identify drugs that block this feedback response and enhance the pro-apoptotic activity of statins, we performed a high-content image-based screen of a 1508 drug library, enriched for FDA-approved compounds. Two of the validated hits, Galeterone (GAL) and Quinestrol, share the cholesterol-related tetracyclic structure, which is also evident in the FDA-approved CRPC drug Abiraterone (ABI). Molecular modeling revealed that GAL, Quinestrol and ABI not only share structural similarity with 25-hydroxy-cholesterol (25HC) but were also predicted to bind similarly to a known protein-binding site of 25HC. This suggested GAL, Quinestrol and ABI are sterol-mimetics and thereby inhibit the statin-induced feedback response. Cell-based assays demonstrated that these agents inhibit nuclear translocation of sterol-regulatory element binding protein 2 (SREBP2) and the transcription of MVA genes. Sensitivity was independent of androgen status and the Fluva-GAL combination significantly impeded CRPC tumor xenograft growth. By identifying cholesterol-mimetic drugs that inhibit SREBP2 activation upon statin treatment, we provide a potent "one-two punch" against CRPC progression and pave the way for innovative therapeutic strategies to combat additional diseases whose etiology is associated with SREBP2 dysregulation.

Keywords: Cholesterol mimetics; Combination therapy; Mevalonate pathway; Prostate cancer; Statin.

MeSH terms

Animals
Apoptosis / drug effects
Cell Death / drug effects
Cell Line, Tumor
Cell Nucleus / drug effects
Cell Nucleus / metabolism
Drug Synergism
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors* / pharmacology
Male
Mice
Mice, Nude
Prostatic Neoplasms* / drug therapy
Prostatic Neoplasms* / metabolism
Prostatic Neoplasms* / pathology
Prostatic Neoplasms, Castration-Resistant / drug therapy
Prostatic Neoplasms, Castration-Resistant / metabolism
Prostatic Neoplasms, Castration-Resistant / pathology
Sterol Regulatory Element Binding Protein 2* / genetics
Sterol Regulatory Element Binding Protein 2* / metabolism
Sterols / pharmacology
Xenograft Model Antitumor Assays

Substances

Sterol Regulatory Element Binding Protein 2
Hydroxymethylglutaryl-CoA Reductase Inhibitors
SREBF2 protein, human
Sterols