Host CYP27A1 expression is essential for ovarian cancer progression
in Endocrine-Related Cancer
Authors: Sisi He 1 , Liqian Ma 1 , Amy E Baek 1 , Anna Vardanyan 1 , Varsha Vembar 1 , Joy J Chen 1 , Adam T Nelson 1 , Joanna E Burdette 2 , 3 and Erik R Nelson 1 , 3 , 4 , 5 , 6
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1 Department of Molecular and Integrative Physiology, University of Illinois at Urbana Champaign, Urbana, Illinois, USA 2 Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois, USA 3 Cancer Center at Illinois, University of Illinois at Urbana Champaign, Urbana, Illinois, USA 4 Division of Nutritional Sciences, University of Illinois at Urbana Champaign, Urbana, Illinois, USA 5 University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, Illinois, USA 6 Carl R. Woese Institute for Genomic Biology, Anticancer Discovery from Pets to People Theme, University of Illinois at Urbana Champaign, Urbana, Illinois, USA
Correspondence should be addressed to E R Nelson: enels@illinois.edu
DOI: https://doi.org/10.1530/ERC-18-0572
Page(s): 659–675
Volume/Issue: Volume 26: Issue 7
Article Type: Research Article
Online Publication Date: Jul 2019
Copyright: © 2019 Society for Endocrinology 2019
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Abstract/Excerpt
Supplementary Materials
There is an urgent need for more effective strategies to treat ovarian cancer. Elevated cholesterol levels are associated with a decreased progression-free survival time (PFS) while statins are protective. 27-Hydroxycholesterol (27HC), a primary metabolite of cholesterol, has been shown to modulate the activities of the estrogen receptors (ERs) and liver x receptors (LXRs) providing a potential mechanistic link between cholesterol and ovarian cancer progression. We found that high expression of CYP27A1, the enzyme responsible for the synthesis of 27HC, was associated with decreased PFS, while high expression of CYP7B1, responsible for 27HC catabolism, was associated with increased PFS. However, 27HC decreased the cellular proliferation of various ovarian cancer cell lines in an LXR-dependent manner. Intriguingly, ID8 grafts were unable to effectively establish in CYP27A1−/− mice, indicating involvement of the host environment. Tumors from mice treated with 27HC had altered myeloid cell composition, and cells from the marrow stem cell lineage were found to be responsible for the effects in CYP27A1−/− mice. While inhibition of CYP27A1 or immune checkpoint did not significantly alter tumor size, their combination did, thereby highlighting this axis as a therapeutic target.
in Endocrine-Related Cancer
Authors: Sisi He 1 , Liqian Ma 1 , Amy E Baek 1 , Anna Vardanyan 1 , Varsha Vembar 1 , Joy J Chen 1 , Adam T Nelson 1 , Joanna E Burdette 2 , 3 and Erik R Nelson 1 , 3 , 4 , 5 , 6
View Less
1 Department of Molecular and Integrative Physiology, University of Illinois at Urbana Champaign, Urbana, Illinois, USA 2 Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois, USA 3 Cancer Center at Illinois, University of Illinois at Urbana Champaign, Urbana, Illinois, USA 4 Division of Nutritional Sciences, University of Illinois at Urbana Champaign, Urbana, Illinois, USA 5 University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, Illinois, USA 6 Carl R. Woese Institute for Genomic Biology, Anticancer Discovery from Pets to People Theme, University of Illinois at Urbana Champaign, Urbana, Illinois, USA
Correspondence should be addressed to E R Nelson: enels@illinois.edu
DOI: https://doi.org/10.1530/ERC-18-0572
Page(s): 659–675
Volume/Issue: Volume 26: Issue 7
Article Type: Research Article
Online Publication Date: Jul 2019
Copyright: © 2019 Society for Endocrinology 2019
Restricted access
48-hour access to this article
USD $30.00
Buy
Check for updates
Citation Alert Citation Alerts
Get Permissions
Abstract/Excerpt
Supplementary Materials
There is an urgent need for more effective strategies to treat ovarian cancer. Elevated cholesterol levels are associated with a decreased progression-free survival time (PFS) while statins are protective. 27-Hydroxycholesterol (27HC), a primary metabolite of cholesterol, has been shown to modulate the activities of the estrogen receptors (ERs) and liver x receptors (LXRs) providing a potential mechanistic link between cholesterol and ovarian cancer progression. We found that high expression of CYP27A1, the enzyme responsible for the synthesis of 27HC, was associated with decreased PFS, while high expression of CYP7B1, responsible for 27HC catabolism, was associated with increased PFS. However, 27HC decreased the cellular proliferation of various ovarian cancer cell lines in an LXR-dependent manner. Intriguingly, ID8 grafts were unable to effectively establish in CYP27A1−/− mice, indicating involvement of the host environment. Tumors from mice treated with 27HC had altered myeloid cell composition, and cells from the marrow stem cell lineage were found to be responsible for the effects in CYP27A1−/− mice. While inhibition of CYP27A1 or immune checkpoint did not significantly alter tumor size, their combination did, thereby highlighting this axis as a therapeutic target.
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