27-Hydroxylation of oncosterone by CYP27A1 switches its activity from pro-tumor to anti-tumor
Oncosterone (6-oxo-cholestane-3β,5α-diol; OCDO) is an oncometabolite and a tumor promoter on estrogen receptor alpha-positive breast cancer (ER(+) BC) and triple-negative breast cancers (TN BC). OCDO is an oxysterol formed in three steps from cholesterol: 1) oxygen addition at the double bond to giv...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227523001529 |
| _version_ | 1797384177708957696 |
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| author | Silia Ayadi Silvia Friedrichs Regis Soulès Laly Pucheu Dieter Lütjohann Sandrine Silvente-Poirot Marc Poirot Philippe de Medina |
| author_facet | Silia Ayadi Silvia Friedrichs Regis Soulès Laly Pucheu Dieter Lütjohann Sandrine Silvente-Poirot Marc Poirot Philippe de Medina |
| author_sort | Silia Ayadi |
| collection | DOAJ |
| description | Oncosterone (6-oxo-cholestane-3β,5α-diol; OCDO) is an oncometabolite and a tumor promoter on estrogen receptor alpha-positive breast cancer (ER(+) BC) and triple-negative breast cancers (TN BC). OCDO is an oxysterol formed in three steps from cholesterol: 1) oxygen addition at the double bond to give α- or β- isomers of 5,6-epoxycholestanols (5,6-EC), 2) hydrolyses of the epoxide ring of 5,6-ECs to give cholestane-3β,5α,6β-triol (CT), and 3) oxidation of the C6 hydroxyl of CT to give OCDO. On the other hand, cholesterol can be hydroxylated by CYP27A1 at the ultimate methyl carbon of its side chain to give 27-hydroxycholesterol ((25R)-Cholest-5-ene-3beta,26-diol, 27HC), which is a tumor promoter for ER(+) BC. It is currently unknown whether OCDO and its precursors can be hydroxylated at position C27 by CYP27A1, as is the impact of such modification on the proliferation of ER(+) and TN BC cells. We investigated, herein, whether 27H-5,6-ECs ((25R)-5,6-epoxycholestan-3β,26-diol), 27H-CT ((25R)-cholestane-3β,5α,6β,26-tetrol) and 27H-OCDO ((25R)-cholestane-6-oxo-3β,5α,26-triol) exist as metabolites and can be produced by cells expressing CYP27A1. We report, for the first time, that these compounds exist as metabolites in humans. We give pharmacological and genetic evidence that CYP27A1 is responsible for their production. Importantly, we found that 27-hydroxy-OCDO (27H-OCDO) inhibits BC cell proliferation and blocks OCDO and 27-HC-induced proliferation in BC cells, showing that this metabolic conversion commutes the proliferative properties of OCDO into antiproliferative ones. These data suggest an unprecedented role of CYP27A1 in the control of breast carcinogenesis by inhibiting the tumor promoter activities of oncosterone and 27-HC. |
| first_indexed | 2024-03-08T21:32:42Z |
| format | Article |
| id | doaj.art-ee27e267e8924c2fa1d3759a0eacd722 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-03-08T21:32:42Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-ee27e267e8924c2fa1d3759a0eacd7222023-12-21T07:29:34ZengElsevierJournal of Lipid Research0022-22752023-12-01641210047927-Hydroxylation of oncosterone by CYP27A1 switches its activity from pro-tumor to anti-tumorSilia Ayadi0Silvia Friedrichs1Regis Soulès2Laly Pucheu3Dieter Lütjohann4Sandrine Silvente-Poirot5Marc Poirot6Philippe de Medina7Cancer Research Center of Toulouse (CRCT), Inserm, CNRS, University of Toulouse, Team INOV:“Cholesterol Metabolism and Therapeutic Innovations”, Toulouse, France; Equipe labellisée par la Ligue Nationale contre le Cancer, Toulouse, France; French Network for Nutrition Physical Acitivity and Cancer Research (NACRe network), Jouy en Josas, FranceInstitute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, GermanyCancer Research Center of Toulouse (CRCT), Inserm, CNRS, University of Toulouse, Team INOV:“Cholesterol Metabolism and Therapeutic Innovations”, Toulouse, France; Equipe labellisée par la Ligue Nationale contre le Cancer, Toulouse, France; French Network for Nutrition Physical Acitivity and Cancer Research (NACRe network), Jouy en Josas, FranceCancer Research Center of Toulouse (CRCT), Inserm, CNRS, University of Toulouse, Team INOV:“Cholesterol Metabolism and Therapeutic Innovations”, Toulouse, France; Equipe labellisée par la Ligue Nationale contre le Cancer, Toulouse, France; French Network for Nutrition Physical Acitivity and Cancer Research (NACRe network), Jouy en Josas, FranceInstitute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, GermanyCancer Research Center of Toulouse (CRCT), Inserm, CNRS, University of Toulouse, Team INOV:“Cholesterol Metabolism and Therapeutic Innovations”, Toulouse, France; For correspondence: Philippe de Medina; Sandrine Silvente-Poirot; Marc PoirotCancer Research Center of Toulouse (CRCT), Inserm, CNRS, University of Toulouse, Team INOV:“Cholesterol Metabolism and Therapeutic Innovations”, Toulouse, France; Equipe labellisée par la Ligue Nationale contre le Cancer, Toulouse, France; French Network for Nutrition Physical Acitivity and Cancer Research (NACRe network), Jouy en Josas, France; For correspondence: Philippe de Medina; Sandrine Silvente-Poirot; Marc PoirotCancer Research Center of Toulouse (CRCT), Inserm, CNRS, University of Toulouse, Team INOV:“Cholesterol Metabolism and Therapeutic Innovations”, Toulouse, France; Equipe labellisée par la Ligue Nationale contre le Cancer, Toulouse, France; French Network for Nutrition Physical Acitivity and Cancer Research (NACRe network), Jouy en Josas, France; For correspondence: Philippe de Medina; Sandrine Silvente-Poirot; Marc PoirotOncosterone (6-oxo-cholestane-3β,5α-diol; OCDO) is an oncometabolite and a tumor promoter on estrogen receptor alpha-positive breast cancer (ER(+) BC) and triple-negative breast cancers (TN BC). OCDO is an oxysterol formed in three steps from cholesterol: 1) oxygen addition at the double bond to give α- or β- isomers of 5,6-epoxycholestanols (5,6-EC), 2) hydrolyses of the epoxide ring of 5,6-ECs to give cholestane-3β,5α,6β-triol (CT), and 3) oxidation of the C6 hydroxyl of CT to give OCDO. On the other hand, cholesterol can be hydroxylated by CYP27A1 at the ultimate methyl carbon of its side chain to give 27-hydroxycholesterol ((25R)-Cholest-5-ene-3beta,26-diol, 27HC), which is a tumor promoter for ER(+) BC. It is currently unknown whether OCDO and its precursors can be hydroxylated at position C27 by CYP27A1, as is the impact of such modification on the proliferation of ER(+) and TN BC cells. We investigated, herein, whether 27H-5,6-ECs ((25R)-5,6-epoxycholestan-3β,26-diol), 27H-CT ((25R)-cholestane-3β,5α,6β,26-tetrol) and 27H-OCDO ((25R)-cholestane-6-oxo-3β,5α,26-triol) exist as metabolites and can be produced by cells expressing CYP27A1. We report, for the first time, that these compounds exist as metabolites in humans. We give pharmacological and genetic evidence that CYP27A1 is responsible for their production. Importantly, we found that 27-hydroxy-OCDO (27H-OCDO) inhibits BC cell proliferation and blocks OCDO and 27-HC-induced proliferation in BC cells, showing that this metabolic conversion commutes the proliferative properties of OCDO into antiproliferative ones. These data suggest an unprecedented role of CYP27A1 in the control of breast carcinogenesis by inhibiting the tumor promoter activities of oncosterone and 27-HC.http://www.sciencedirect.com/science/article/pii/S0022227523001529CYP27A1oxysterols5,6-epoxycholestanolcholestane-3β,5α,6β-trioloncosteronemetabolism |
| spellingShingle | Silia Ayadi Silvia Friedrichs Regis Soulès Laly Pucheu Dieter Lütjohann Sandrine Silvente-Poirot Marc Poirot Philippe de Medina 27-Hydroxylation of oncosterone by CYP27A1 switches its activity from pro-tumor to anti-tumor Journal of Lipid Research CYP27A1 oxysterols 5,6-epoxycholestanol cholestane-3β,5α,6β-triol oncosterone metabolism |
| title | 27-Hydroxylation of oncosterone by CYP27A1 switches its activity from pro-tumor to anti-tumor |
| title_full | 27-Hydroxylation of oncosterone by CYP27A1 switches its activity from pro-tumor to anti-tumor |
| title_fullStr | 27-Hydroxylation of oncosterone by CYP27A1 switches its activity from pro-tumor to anti-tumor |
| title_full_unstemmed | 27-Hydroxylation of oncosterone by CYP27A1 switches its activity from pro-tumor to anti-tumor |
| title_short | 27-Hydroxylation of oncosterone by CYP27A1 switches its activity from pro-tumor to anti-tumor |
| title_sort | 27 hydroxylation of oncosterone by cyp27a1 switches its activity from pro tumor to anti tumor |
| topic | CYP27A1 oxysterols 5,6-epoxycholestanol cholestane-3β,5α,6β-triol oncosterone metabolism |
| url | http://www.sciencedirect.com/science/article/pii/S0022227523001529 |
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