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

Autor: Sandrine Silvente-Poirot, Marc Poirot, Florence Dalenc, Regis Soules, Arnaud Mallinger
Přispěvatelé: Poirot, Marc, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was funded by the Institut National de la Santé et de la Recherche Médicale, the Université de Toulouse, the Association pour la Recherche sur le Cancer Projet PJA 20131200342, the French National Cancer Institute Grant PRTK-K15-118 and the Initiatives d'Excellence (IDEX), Actions Thématiques Stratégiques (ATS) InnoVinBC, the Fondation de France (R11166BB), and the associations « pour Céline » and « Flo »., Institut Claudius-Regaud [IUCT-O, Toulouse], Institut Universitaire du Cancer Toulouse - Oncopôle (IUCT)
Rok vydání: 2018
Předmět:
0301 basic medicine
Oxysterol
[SDV]Life Sciences [q-bio]
Metabolite
Breast Neoplasms
[SDV.CAN]Life Sciences [q-bio]/Cancer
medicine.disease_cause
Biochemistry
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Glucocorticoid receptor
[SDV.CAN] Life Sciences [q-bio]/Cancer
[SDV.BBM] Life Sciences [q-bio]/Biochemistry
Molecular Biology
medicine
Animals
Humans
[SDV.BBM]Life Sciences [q-bio]/Biochemistry
Molecular Biology
[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Biochemistry [q-bio.BM]
[SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry
Molecular Biology/Biochemistry [q-bio.BM]
Carcinogen
[SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism
chemistry.chemical_classification
[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology
General Medicine
[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism
[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Biomolecules [q-bio.BM]
[SDV] Life Sciences [q-bio]
[SDV.AEN] Life Sciences [q-bio]/Food and Nutrition
Cholesterol
030104 developmental biology
Enzyme
Mechanism of action
chemistry
030220 oncology & carcinogenesis
Cancer cell
Carcinogens
Female
medicine.symptom
Carcinogenesis
[SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Zdroj: Biochimie
Biochimie, 2018, 153, pp.139-149. ⟨10.1016/j.biochi.2018.04.008⟩
Biochimie, Elsevier, 2018, 153, pp.139-149. ⟨10.1016/j.biochi.2018.04.008⟩
ISSN: 0300-9084
DOI: 10.1016/j.biochi.2018.04.008
Popis: International audience; Oxygenation products of cholesterol, named oxysterols, were suspected since the 20th century to be involved in carcinogenesis. Among the family of oxysterol molecules, cholesterol-5,6-epoxides (5,6-EC) retained the attention of scientists because they contain a putative alkylating epoxide group. However, studies failed into demonstrating that 5,6-EC were direct carcinogens and revealed a surprising chemical stability and unreactivity towards nucleophiles in standard conditions. Analyses of 5,6-EC metabolism in normal cells showed that they were extensively transformed into cholestane-3β,5α,6β-triol (CT) by the cholesterol-5,6-epoxide hydrolase (ChEH). Studies performed in cancer cells showed that CT was additionally metabolized into an oxysterol identified as the 6-oxo-cholestan-3β,5α-diol (OCDO), by the 11β-hydroxysteroid dehydrogenase of type 2 (HSD2), the enzyme which inactivates cortisol into cortisone. Importantly, OCDO was shown to display tumor promoter properties in breast cancers, by binding to the glucocorticoid receptor, and independently of their estrogen receptor status, revealing the existence of a new tumorigenic pathway centered on 5,6-EC. In breast tumors from patients, OCDO production as well as the expression of the enzymes involved in the pathway producing OCDO, namely ChEH subunits and HSD2, were higher compared to normal tissues, and overexpression of these enzymes correlate with a higher risk of patient death, indicating that this onco-metabolism is of major importance to breast cancer pathology. Herein, we will review the actual knowledge and the future trends in OCDO chemistry, biochemistry, metabolism and mechanism of action and will discuss the impact of OCDO discovery on new anticancer therapeutic strategies.
Databáze: OpenAIRE
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