Journal article
Tumor-Suppressive and Immune-Stimulating Roles of Cholesterol 25-hydroxylase in Pancreatic Cancer Cells
Molecular cancer research, Vol.21(3), pp.228-239
03/01/2023
DOI: 10.1158/1541-7786.MCR-22-0602
PMCID: PMC9992122
PMID: 36378658
Abstract
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.
Loss of CH25H by pancreatic cancer cells may stimulate tumor progression and interfere with immunotherapies.
Details
- Title: Subtitle
- Tumor-Suppressive and Immune-Stimulating Roles of Cholesterol 25-hydroxylase in Pancreatic Cancer Cells
- Creators
- Noreen McBrearty - University of PennsylvaniaChristina Cho - University of PennsylvaniaJinyun Chen - University of PennsylvaniaFarima Zahedi - University of PennsylvaniaAmy R Peck - Medical College of WisconsinEnrico Radaelli - University of PennsylvaniaCharles-Antoine Assenmacher - University of PennsylvaniaClarice Pavlak - University of PennsylvaniaAnne Devine - University of PennsylvaniaPengfei Yu - University of PennsylvaniaZhen Lu - University of PennsylvaniaHongru Zhang - University of PennsylvaniaJinyang Li - University of PennsylvaniaJason R Pitarresi - University of PennsylvaniaIgor Astsaturov - Fox Chase Cancer CenterEdna Cukierman - Fox Chase Cancer CenterAnil K Rustgi - Columbia University Irving Medical CenterBen Z Stanger - University of PennsylvaniaHallgeir Rui - Medical College of WisconsinSerge Y Fuchs - University of Pennsylvania
- Resource Type
- Journal article
- Publication Details
- Molecular cancer research, Vol.21(3), pp.228-239
- DOI
- 10.1158/1541-7786.MCR-22-0602
- PMID
- 36378658
- PMCID
- PMC9992122
- NLM abbreviation
- Mol Cancer Res
- ISSN
- 1541-7786
- eISSN
- 1557-3125
- Grant note
- R21 CA231252 / NCI NIH HHS R01 CA269660 / NCI NIH HHS S10 OD023465 / NIH HHS R21 CA252535 / NCI NIH HHS P30 CA006927 / NCI NIH HHS T32 CA115299 / NCI NIH HHS CA098756 / National Cancer Institute (NCI) R01 CA240814 / NCI NIH HHS CA016520 / National Cancer Institute (NCI) S10 OD023666 / NIH HHS
- Language
- English
- Date published
- 03/01/2023
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984949216202771
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