1. Pharmacologic and genetic inhibition of cholesterol esterification enzymes reduces tumour burden: A systematic review and meta-analysis of preclinical models
- Author
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Marc Poirot, Ruoying Wu, Thomas A. Hughes, Xinyu Chen, Michael A. Zulyniak, Xinyu Luo, Philip Chalmers, Alex Websdale, Mengfan Xu, Giorgia Cioccoloni, James L. Thorne, Rufaro Mwarzi, Yi Kiew, Hanne Roberg-Larsen, University of Leeds, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Oslo (UiO), Poirot, Marc, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
Coenzyme A ,[SDV]Life Sciences [q-bio] ,Organic Anion Transporters ,Antineoplastic Agents ,Pharmacology ,Biochemistry ,Metastasis ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Lipid droplet ,medicine ,Animals ,Humans ,Urea ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,Clinical Trials as Topic ,Esterification ,Chemistry ,Cholesterol ,Anticholesteremic Agents ,Cancer ,medicine.disease ,Xenograft Model Antitumor Assays ,3. Good health ,Tumor Burden ,[SDV] Life Sciences [q-bio] ,Enzyme ,Apoptosis ,030220 oncology & carcinogenesis ,Cholesteryl ester - Abstract
International audience; Cholesterol esterification proteins Sterol-O acyltransferases (SOAT) 1 and 2 are emerging prognostic markers in many cancers. These enzymes utilise fatty acids conjugated to coenzyme A to esterify cholesterol. Cholesterol esterification is tightly regulated and enables formation of lipid droplets that act as storage organelles for lipid soluble vitamins and minerals, and as cholesterol reservoirs. In cancer, this provides rapid access to cholesterol to maintain continual synthesis of the plasma membrane. In this systematic review and meta-analysis, we summarise the current depth of understanding of the role of this metabolic pathway in pan-cancer development. A systematic search of PubMed, Scopus, Web of Science, and Cochrane Library for preclinical studies identified eight studies where cholesteryl ester concentrations were compared between tumour and adjacent-normal tissue, and 24 studies where cholesterol esterification was blocked by pharmacological or genetic approaches. Tumour tissue had a significantly greater concentration of cholesteryl esters than non-tumour tissue (p < 0.0001). Pharmacological or genetic inhibition of SOAT was associated with significantly smaller tumours of all types (p ≤ 0.002). SOAT inhibition increased tumour apoptosis (p = 0.007), CD8 + lymphocyte infiltration and cytotoxicity (p ≤ 0.05), and reduced proliferation (p = 0.0003) and metastasis (p < 0.0001). Significant risk of publication bias was found and may have contributed to a 32% overestimation of the meta-analysed effect size. Avasimibe, the most frequently used SOAT inhibitor, was effective at doses equivalent to those previously reported to be safe and tolerable in humans. This work indicates that SOAT inhibition should be explored in clinical trials as an adjunct to existing anti-neoplastic agents.
- Published
- 2021