Tumor-Suppressive and Immune-Stimulating Roles of Cholesterol 25-hydroxylase in Pancreatic Cancer Cells.

Autor:	McBrearty N; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Cho C; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Chen J; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Zahedi F; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Peck AR; Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin., Radaelli E; Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Assenmacher CA; Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Pavlak C; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Devine A; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Yu P; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Lu Z; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Zhang H; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Li J; Department of Pathology and Laboratory Medicine, Perelman School of Medicine and Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania., Pitarresi JR; Department of Pathology and Laboratory Medicine, Perelman School of Medicine and Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania., Astsaturov I; Marvin and Concetta Greenberg Pancreatic Cancer Institute, Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Cukierman E; Marvin and Concetta Greenberg Pancreatic Cancer Institute, Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Rustgi AK; Division of Digestive and Liver Diseases, Department of Medicine, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York., Stanger BZ; Department of Pathology and Laboratory Medicine, Perelman School of Medicine and Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania., Rui H; Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin., Fuchs SY; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Jazyk:	angličtina
Zdroj:	Molecular cancer research : MCR [Mol Cancer Res] 2023 Mar 01; Vol. 21 (3), pp. 228-239.
DOI:	10.1158/1541-7786.MCR-22-0602
Abstrakt:	Cholesterol dependence is an essential characteristic of pancreatic ductal adenocarcinoma (PDAC). Cholesterol 25-hydroxylase (CH25H) catalyzes monooxygenation of cholesterol into 25-hydroxycholesterol, which is implicated in inhibiting cholesterol biosynthesis and in cholesterol depletion. Here, we show that, within PDAC cells, accumulation of cholesterol was facilitated by the loss of CH25H. Methylation of the CH25H gene and decreased levels of CH25H expression occurred in human pancreatic cancers and was associated with poor prognosis. Knockout of Ch25h in mice accelerated progression of Kras-driven pancreatic intraepithelial neoplasia. Conversely, restoration of CH25H expression in human and mouse PDAC cells decreased their viability under conditions of cholesterol deficit, and decelerated tumor growth in immune competent hosts. Mechanistically, the loss of CH25H promoted autophagy resulting in downregulation of MHC-I and decreased CD8+ T-cell tumor infiltration. Re-expression of CH25H in PDAC cells combined with immune checkpoint inhibitors notably inhibited tumor growth. We discuss additional benefits that PDAC cells might gain from inactivation of CH25H and the potential translational importance of these findings for therapeutic approaches to PDAC. Implications: Loss of CH25H by pancreatic cancer cells may stimulate tumor progression and interfere with immunotherapies. (©2022 American Association for Cancer Research.)
Databáze:	MEDLINE
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