Host CYP27A1 expression is essential for ovarian cancer progression

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.

Phytosterols and phytostanols and the hallmarks of cancer in model organisms: A systematic review and meta-analysis

“…However, the cellular receptors for PSS have not been clearly identified in the context of cancer cell biology. Previously, PSS was shown to dampen the effect of oxysterols in breast cancer (Hutchinson et al 2019), and oxysterols are now considered strong mediators of the pathophysiology of several cancers (Baek et al 2017;Segala et al 2017;He et al 2019). Further mechanistic evidence could be provided by applying emerging technologies such as phage display high throughput screens (Dilly et al 2017) to panels of PSS to identify cellular protein receptors to which PSS directly bind.…”

Phytosterols and phytostanols and the hallmarks of cancer: a meta-analysis of pre-clinical animal models

“…However, the cellular receptors for PSS have not been clearly identified in the context of cancer cell biology. Previously, PSS were shown to dampen the effect of oxysterols in breast cancer (Hutchinson, Lianto, Moore, Hughes & Thorne, 2019), and oxysterols are now considered strong mediators of the pathophysiology of several cancers (Baek et al, 2017;He et al, 2019;Segala et al, 2017). Further mechanistic evidence could be provided by applying emerging technologies such as phage display high throughput screens (Dilly et al, 2017) to panels of PSS to identify cellular protein receptors to which PSS directly bind.…”

Aberrant Cholesterol Metabolism in Ovarian Cancer: Identification of Novel Therapeutic Targets

“…In addition, LDL, a main blood carrier of cholesterol, and large amounts of cholesterol are associated with aggressiveness and poor survival outcomes of ovarian cancer (99). In the murine ID8 model of ovarian cancer, mice subjected to a high cholesterol diet exhibited increased tumor growth compared to that observed in the control groups (24). Dysregulated cholesterol homeostasis has been reported to enhance platinum resistance in ovarian cancer (22).…”

“…Recently, considerable evidence supporting the importance of reprogrammed cholesterol metabolism in ovarian cancer has been reported. Highly expressed proteins and enzymes involved in cholesterol metabolism promote ovarian cancer progression; cholesterol and its derivatives also contribute to proliferation and chemoresistance in ovarian cancer and have roles in the immunosuppressive tumor microenvironment (22)(23)(24)(25). Here, we have systematically summarized the most recent findings on cholesterol and its derivatives in ovarian cancer, with the aim of comprehensively understanding their specific functions to facilitate the identification of novel markers and therapeutic targets.…”