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Overcoming statin resistance in prostate cancer cells by targeting the 3-hydroxy-3-methylglutaryl-CoA-reductase.

التفاصيل البيبلوغرافية
العنوان: Overcoming statin resistance in prostate cancer cells by targeting the 3-hydroxy-3-methylglutaryl-CoA-reductase.
المؤلفون: Göbel A; Mildred Scheel Early Career Center, Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany; Center for Healthy Ageing, Department of Medicine III, Technische Universität Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address: andy.goebel@ukdd.de., Pählig S; Mildred Scheel Early Career Center, Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany; Center for Healthy Ageing, Department of Medicine III, Technische Universität Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany., Motz A; Mildred Scheel Early Career Center, Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany., Breining D; Mildred Scheel Early Career Center, Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany., Traikov S; Max Planck Institute for Molecular Cell Biology and Genetics, Dresden, Germany., Hofbauer LC; Mildred Scheel Early Career Center, Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany; Center for Healthy Ageing, Department of Medicine III, Technische Universität Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany., Rachner TD; Mildred Scheel Early Career Center, Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany; Center for Healthy Ageing, Department of Medicine III, Technische Universität Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
المصدر: Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2024 May 28; Vol. 710, pp. 149841. Date of Electronic Publication: 2024 Mar 28.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier Country of Publication: United States NLM ID: 0372516 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2104 (Electronic) Linking ISSN: 0006291X NLM ISO Abbreviation: Biochem Biophys Res Commun Subsets: MEDLINE
أسماء مطبوعة: Publication: <2002- >: San Diego, CA : Elsevier
Original Publication: New York, Academic Press.
مواضيع طبية MeSH: Hydroxymethylglutaryl-CoA Reductase Inhibitors*/pharmacology , Prostatic Neoplasms*/drug therapy , Prostatic Neoplasms*/genetics , Acyl Coenzyme A*, Male ; Humans ; Hydroxymethylglutaryl CoA Reductases/genetics ; Hydroxymethylglutaryl CoA Reductases/metabolism ; Sterol Regulatory Element Binding Protein 1 ; Simvastatin/pharmacology ; Caspases ; Dipyridamole
مستخلص: Prostate cancer is the most prevalent malignancy in men. While diagnostic and therapeutic interventions have substantially improved in recent years, disease relapse, treatment resistance, and metastasis remain significant contributors to prostate cancer-related mortality. Therefore, novel therapeutic approaches are needed. Statins are inhibitors of the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway which plays an essential role in cholesterol homeostasis. Numerous preclinical studies have provided evidence for the pleiotropic antitumor effects of statins. However, results from clinical studies remain controversial and have shown substantial benefits to even no effects on human malignancies including prostate cancer. Potential statin resistance mechanisms of tumor cells may account for such discrepancies. In our study, we treated human prostate cancer cell lines (PC3, C4-2B, DU-145, LNCaP) with simvastatin, atorvastatin, and rosuvastatin. PC3 cells demonstrated high statin sensitivity, resulting in a significant loss of vitality and clonogenic potential (up to - 70%; p < 0.001) along with an activation of caspases (up to 4-fold; p < 0.001). In contrast, C4-2B and DU-145 cells were statin-resistant. Statin treatment induced a restorative feedback in statin-resistant C4-2B and DU-145 cells through upregulation of the HMGCR gene and protein expression (up to 3-folds; p < 0.01) and its transcription factor sterol-regulatory element binding protein 2 (SREBP-2). This feedback was absent in PC3 cells. Blocking the feedback using HMGCR-specific small-interfering (si)RNA, the SREBP-2 activation inhibitor dipyridamole or the HMGCR degrader SR12813 abolished statin resistance in C4-2B and DU-145 and induced significant activation of caspases by statin treatment (up to 10-fold; p < 0.001). Consistently, long-term treatment with sublethal concentrations of simvastatin established a stable statin resistance of a PC3 SIM subclone accompanied by a significant upregulation of both baseline as well as post-statin HMGCR protein (gene expression up to 70-fold; p < 0.001). Importantly, the statin-resistant phenotype of PC3 SIM cells was reversible by HMGCR-specific siRNA and dipyridamole. Our investigations reveal a key role of a restorative feedback driven by the HMGCR/SREBP-2 axis in statin resistance mechanisms of prostate cancer cells.
Competing Interests: Declaration of competing interest The authors have received honoraria, unrestricted educational grants and research funding from to the individual or the institution by Alexion (LCH), Amgen (LCH, TDR), Ascendis (LCH), Pharmacosmos (LCH), and UCB (LCH, TDR). All other authors declare no potential conflicts of interest.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
فهرسة مساهمة: Keywords: 3-Hydroxy-3-methylglutaryl-CoA reductase; Mevalonate pathway; Prostate cancer; Resistance mechanisms; Statins
المشرفين على المادة: 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors)
EC 1.1.1.- (Hydroxymethylglutaryl CoA Reductases)
1553-55-5 (3-hydroxy-3-methylglutaryl-coenzyme A)
0 (Sterol Regulatory Element Binding Protein 1)
AGG2FN16EV (Simvastatin)
EC 3.4.22.- (Caspases)
64ALC7F90C (Dipyridamole)
0 (Acyl Coenzyme A)
تواريخ الأحداث: Date Created: 20240408 Date Completed: 20240422 Latest Revision: 20240422
رمز التحديث: 20240422
DOI: 10.1016/j.bbrc.2024.149841
PMID: 38588613
قاعدة البيانات: MEDLINE
الوصف
تدمد:1090-2104
DOI:10.1016/j.bbrc.2024.149841