Chemistry, biochemistry, metabolic fate and mechanism of action of 6-oxo-cholestan-3β,5α-diol (OCDO), a tumor promoter and cholesterol metabolite

Poirot, Marc; Soulès, Régis; Mallinger, Arnaud; Silvente-Poirot, Sandrine

doi:10.1016/j.biochi.2018.04.008

Cited by 21 publications

(19 citation statements)

References 96 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…25HC can also be produced by cholesterol autoxidation in addition to being produced by the 25-hydroxylase enzyme, whereas 27HC is only produced by an enzymatic transformation of cholesterol. Cholesterol-rich processed foods contain high amounts of 5,6ECs and CT (2,4), the mandatory precursors of OCDO (15), while OCDO and 25HC, in lower amounts, have been reported in some studies (2,4). This suggests that processed foods containing OCDO or its precursors, which can be transformed into OCDO when the OCDO biosynthetic pathway is upregulated in tumors, could lead to an increase in tumor growth (15).…”

Section: Oxysterols Cholesterol-rich Foods and Cancersmentioning

confidence: 99%

“…In normal cells, cholesterol biosynthesis is tightly regulated and is controlled by cholesterol itself and by some oxysterols (3). Oxysterols are products of cholesterol oxygenation on the steroid backbone rings or on the aliphatic sidechain that can be generated by enzymes or by autoxidation processes in the presence of free reactive oxygen species or indirectly through lipoperoxidation (2,4). Endogenous oxysterols, including 22(R)-hydroxycholesterol [22(R)HC]; 24(S)hydroxycholesterol [24(S)HC]; 25-hydroxycholesterol (25HC), 7a-hydroxycholesterol (7aHC), 27-hydroxycholesterol (27HC), 5,6a-epoxycholesterol (5,6a-EC); and 5,6b-epoxycholesterol (5,6b-EC) are known liver X receptor (LXR) ligands, activating LXR responses at physiologic range concentrations (mmol/L; refs.…”

Section: Cholesterol Biosynthesis In Normal and Cancer Cellsmentioning

confidence: 99%

“…Interestingly, an oncometabolism downstream of 5,6a-EC and 5,6b-EC (5,6EC) was identified in breast cancer in human and animal models (15). The cholesterol epoxide hydrolase (ChEH), formed by the D8D7I and 3b-hydroxysterol-D 7 -reductase (DHCR7) enzymes, is known to metabolize 5,6-ECs into cholestane-3b,5a,6b-triol (CT) in normal tissues (4,16). In breast cancer, the ChEH transforms 5,6ECs into CT that is further transformed into 6-oxo-cholestan-3b,5a-diol (OCDO) by 11bhydroxysteroid-dehydrogenase-type-2 (11bHSD2), the enzyme inactivating cortisol into cortisone.…”

Section: Oxysterols As Oncopromoter Metabolites Targeting Nuclear Recmentioning

confidence: 99%

“…5,6ECs are produced mainly by cholesterol autoxidation, although an enzymatic reaction has also been proposed, while CT is not a spontaneous product of oxidation (4). 25HC can also be produced by cholesterol autoxidation in addition to being produced by the 25-hydroxylase enzyme, whereas 27HC is only produced by an enzymatic transformation of cholesterol.…”

Section: Oxysterols Cholesterol-rich Foods and Cancersmentioning

confidence: 99%

See 3 more Smart Citations

The Effects of Cholesterol-Derived Oncometabolites on Nuclear Receptor Function in Cancer

2018

Self Cite

View full text Add to dashboard Cite

Epidemiologic studies are controversial concerning the roles played by cholesterol in cancer risk and development, possibly as it is not cholesterol per se that is pathologic in cancers. Indeed, recent data reveal that the cholesterol metabolism in cancer cells can generate endogenous oncopromoter metabolites at higher levels compared with normal tissues and/or can be deregulated in the production of endogenous oncosuppressor metabolites in an opposite way. These metabolites are oxysterols, which are cholesterol oxygenation products generated by enzymatic and/or autoxidation processes. All these oxysterols are new classes of estrogen, glucocorticoid, or liver X nuclear receptor ligands, and their protumor action on their cognate receptors could explain some drug resistance, while treatment with antitumor metabolites could complement their deficiency in cancers and restore their action on their nuclear receptor. Given that hypercholesterolemia and high intakes of cholesterol-rich foods or processed foods can generate these oxysterols, their importance in cancer risk or development in overweight and obese people is to be considered. The discovery of these cholesterol-derived metabolites and the identification of the nuclear receptors mediating their pro- or antitumor activities are important findings, which should have major implications in the diagnosis, prevention, and treatment of different cancers and open new areas of research. .

show abstract

Section: Oxysterols Cholesterol-rich Foods and Cancersmentioning

confidence: 99%

Section: Cholesterol Biosynthesis In Normal and Cancer Cellsmentioning

confidence: 99%

Section: Oxysterols As Oncopromoter Metabolites Targeting Nuclear Recmentioning

confidence: 99%

Section: Oxysterols Cholesterol-rich Foods and Cancersmentioning

confidence: 99%

See 2 more Smart Citations

The Effects of Cholesterol-Derived Oncometabolites on Nuclear Receptor Function in Cancer

2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…Elevated expression of the cholesterol-biosynthesis pathway is strongly associated with poor prognosis in the majority of solid tumors including breast cancer. Intra-tumor accumulation of cholesterol esters and metabolites is correlated with tumor cell hyper-proliferation, metastasis, stemness, and therapeutic resistance 2–7 . Deregulated cholesterol-biosynthesis flux or expression of the pathway enzymes could be tumor driving 3,8,9 .…”

Section: Introductionmentioning

confidence: 99%

RORγ is a targetable master regulator of cholesterol biosynthesis in a cancer subtype

et al. 2019

View full text Add to dashboard Cite

Tumor subtype-specific metabolic reprogrammers could serve as targets of therapeutic intervention. Here we show that triple-negative breast cancer (TNBC) exhibits a hyper-activated cholesterol-biosynthesis program that is strongly linked to nuclear receptor RORγ, compared to estrogen receptor-positive breast cancer. Genetic and pharmacological inhibition of RORγ reduces tumor cholesterol content and synthesis rate while preserving host cholesterol homeostasis. We demonstrate that RORγ functions as an essential activator of the entire cholesterol-biosynthesis program, dominating SREBP2 via its binding to cholesterol-biosynthesis genes and its facilitation of the recruitment of SREBP2. RORγ inhibition disrupts its association with SREBP2 and reduces chromatin acetylation at cholesterol-biosynthesis gene loci. RORγ antagonists cause tumor regression in patient-derived xenografts and immune-intact models. Their combination with cholesterol-lowering statins elicits superior anti-tumor synergy selectively in TNBC. Together, our study uncovers a master regulator of the cholesterol-biosynthesis program and an attractive target for TNBC.

show abstract

Therapeutic Applications of Oxysterols and Derivatives in Age-Related Diseases, Infectious and Inflammatory Diseases, and Cancers

Ksila,

Ghzaiel,

Sassi

et al. 2023

Implication of Oxysterols and Phytosterols in Aging and Human Diseases

View full text Add to dashboard Cite

Chemistry, biochemistry, metabolic fate and mechanism of action of 6-oxo-cholestan-3β,5α-diol (OCDO), a tumor promoter and cholesterol metabolite

Cited by 21 publications

References 96 publications

The Effects of Cholesterol-Derived Oncometabolites on Nuclear Receptor Function in Cancer

The Effects of Cholesterol-Derived Oncometabolites on Nuclear Receptor Function in Cancer

RORγ is a targetable master regulator of cholesterol biosynthesis in a cancer subtype

Therapeutic Applications of Oxysterols and Derivatives in Age-Related Diseases, Infectious and Inflammatory Diseases, and Cancers

Contact Info

Product

Resources

About