Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 659-675 |
| Number of pages | 17 |
| Journal | Endocrine-Related Cancer |
| Volume | 26 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jan 1 2019 |
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Keywords
- 27-hydroxycholesterol
- Cholesterol
- Myeloid-derived suppressor cells
- Ovarian cancer
- Tumor microenvironment
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Oncology
- Endocrinology
- Cancer Research
Cite this
Host CYP27A1 expression is essential for ovarian cancer progression. / He, Sisi; Ma, Liqian; Baek, Amy E.; Vardanyan, Anna; Vembar, Varsha; Chen, Joy J.; Nelson, Adam T.; Burdette, Joanna E.; Nelson, Erik.
In: Endocrine-Related Cancer, Vol. 26, No. 7, 01.01.2019, p. 659-675.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Host CYP27A1 expression is essential for ovarian cancer progression
AU - He, Sisi
AU - Ma, Liqian
AU - Baek, Amy E.
AU - Vardanyan, Anna
AU - Vembar, Varsha
AU - Chen, Joy J.
AU - Nelson, Adam T.
AU - Burdette, Joanna E.
AU - Nelson, Erik
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
KW - 27-hydroxycholesterol
KW - Cholesterol
KW - Myeloid-derived suppressor cells
KW - Ovarian cancer
KW - Tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85068823285&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85068823285&partnerID=8YFLogxK
U2 - 10.1530/ERC-18-0572
DO - 10.1530/ERC-18-0572
M3 - Article
C2 - 31048561
AN - SCOPUS:85068823285
VL - 26
SP - 659
EP - 675
JO - Endocrine-Related Cancer
JF - Endocrine-Related Cancer
SN - 1351-0088
IS - 7
ER -