When cholesterol meets histamine, it gives rise to dendrogenin A: a tumour suppressor metabolite1 Marc Poirot, Sandrine Silvente-Poirot
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Marc Poirot, Sandrine Silvente-Poirot. When cholesterol meets histamine, it gives rise to dendrogenin A: a tumour suppressor metabolite1. Biochemical Society Transactions, Portland Press, 2016, 44 (2), pp.631-637. 10.1042/BST20150232. inserm-02380631
HAL Id: inserm-02380631 https://www.hal.inserm.fr/inserm-02380631 Submitted on 26 Nov 2019
HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Downloaded from https://portlandpress.com/biochemsoctrans/article-pdf/44/2/631/432210/bst0440631.pdf by INSERM DISC IST user on 26 November 2019 5th European Lipidomic Meeting BC ) ance 1 + ( -EC) with histamine α -oestradiol and protects rodents 2016 Authors; published by Portland Press Limited 631 C β and prevents breast cancer in vivo and -epoxycholesterol and amines with α BC) [10]. This led to the clinical development of -epoxycholesterol (5,6 ) α + ( in vitro pharmacological properties Tam for the treatment and chemoprevention of ER Dendrogenins: products of the conjugation of 5,6 Pharmacogenomic studies were usedas to a identify hetero-oligomeric the AEBS complex made up of two subunits personalized medicine. One of the first targeted therapiesthe was hormonotherapy of breast cancersoestrogen receptor (BCs) with the expressing drug tamoxifen the (Tam; Figure 1A). V. Craig Jordanmitogenic first effects demonstrated of thatagainst the 17 Tam development of blocks oestrogen(ER receptor-positive the BCs [11]. It was laterpharmacology found that than Tam displaysmolecular expected target a called the more antioestrogen-binding [12,13] site complex (AEBS) was and identified an [14].anticancer This additional pharmacology was of Tam shown thanks toof to the selective AEBS development contribute ligands with to noPBPE affinity the and for DPPE the (Figure ER 1A) such [12,14–32]. as Thesepaved observations the way forcholesterol the biosynthesis and identification the of metabolism5,6-epoxides new of that parameters cholesterol- are in involvedand in resistance the control tooutcomes of of sensitivity these Tam studies was [18].A the (DDA; discovery One of Figure dendrogenin 1B), of asuppressing properties cholesterol the whose metabolite production with is most tumour impairedoncogenesis during [8,9,33]. exciting The discovery ofnew DDA promising has opportunities opened for up cancerroutes treatments to and understand new the aetiology of cancers. - - 7 α -EC, 5,6 α 1 -hydroxysteroid- β -isomerase; DDA, dendrogenin 7 , 8 -hydroxysteroid- β -epoxycholesterol; ChEH, cholesterol-5,6-epoxide hydrolase; CT, β and Sandrine Silvente-Poirot*† -EC, 5,6 1 β -triol; D8D7I, EBP, 3 β ,6 Abstract Dendrogenin A (DDA) isarises the from the first stereoselective steroidal enzymatic alkaloid conjugation of (SA) 5,6 to be identified in human tissues to date and (HA). DDA induces the(BC) re-differentiation and melanoma of development cancer inDDA cells mice, production evidencing is lower its in protective BCsduring role compared carcinogenesis. against with The oncogenesis. normal discovery tissues, of In DDA suggesting addition, which reveals a the deregulation lies existence of at of its a the biosynthesis newmetabolic crossroads metabolic tumour pathway of suppressor. in cholesterol mammals and HA metabolism and which leads to the production of this α AEBS, microsomal antioestrogen-binding site; BC, breast cancer; 5,6 ,5 cancer, cholesterol, cholesterol-5,6-epoxide hydrolase, dendrogenin, steroidal β
Cancers are among the leading causes of death in the Correspondence may be addressed to either author (email [email protected] or Institut Claudius Regaud, Institut Universitaire du Cancer, F-31059 Toulouse, France Biochem. Soc. Trans. (2016) 44, 631–637; doi:10.1042/BST20150232 1 alkaloid, tamoxifen. Abbreviations: Key words: world and many aspects of theirglobal diagnoses unmet and treatment medical are needs.in Great our progress understanding has of these been diseases,nificantly made which improved has in their turn management, sig- particularlythe through development of targeted therapies and the emergence of Cholesterol is a crucial component of cell membranes. Itan plays important role in the organization ofis the lipid essential bilayers for and membraneIn biogenesis and addition cell to proliferation. active metabolism these that leads roles,structural to classes cholesterol the of production sterol is of lipids,bile different such subject acids, as sterol to steroid conjugates hormones, thought and an that oxysterols. It bilerepresented was various acids, ways initially of storing or oxysterols eliminating cholesterol to and preserve sterol cholesterol homoeostasis, conjugates genetic however and more functional genomic recent studies nowthat strongly suggest they play physiological functionsthe identification [1,2]. of sterol This metabolites has that display ledfunctions important in to the immune system [3–5],system in [6,7] the and central in nervous pathologies such as cancer [8,9]. Introduction epoxycholesterol; 5,6 *Sterol Metabolism and Therapeutic Innovations, Cancer Research Center of Toulouse, INSERM UMR 1037, University of Toulouse, F-31037 Toulouse, Fr dendrogenin A: a tumour suppressorMarc Poirot*† metabolite † When cholesterol meets histamine, it gives rise to 5th European Lipidomic Meeting [email protected]). cholestane-3 A; DDAs, dendrogenin A synthase; DDB, dendrogenin B; DHCR7, 3 reductase; DPPE, tesmilifene;steroidal alkaloid; tamoxifen, PBPE, Tam. 1-[2-[4-(phenylmethyl)phenoxy]ethyl]-Pyrrolidine; SA, 632 Biochemical Society Transactions (2016) Volume 44, part 2
Figure 1 Chemical structure of compounds (A)Tam,PBPEandDPPE;(B) DDA and DDB. Downloaded from https://portlandpress.com/biochemsoctrans/article-pdf/44/2/631/432210/bst0440631.pdf by INSERM DISC IST user on 26 November 2019
involved in cholesterol biosynthesis: the 3β-hydroxysteroid- 5,6-EC metabolism could be involved in organogenesis 8,7-isomerase (D8D7I, also called EBP) and the 3β- and cell differentiation [8]. To test this hypothesis, the hydroxysteroid-7-reductase (DHCR7) [14]. It was later putative metabolites described above were tested in vitro to found that these subunits catalysed the enzymatic activity of determine if they could induce cell differentiation. Cancer cholesterol-5,6-epoxide hydrolase (ChEH) and that D8D7I cells were first used because they are dedifferentiated cells was the catalytic subunit of ChEH and DHCR7 the and some have been shown to undergo re-differentiation regulatory subunit [20]. ChEH catalyses the hydration of 5,6- following specific treatment [8,36]. In vitro tests showed epoxycholesterols (5,6-ECs) to give cholestane-3β,5α,6β- that, among the different molecules tested, 5α-hydroxy-6β- triol (CT; Figure 2) [17]. Tam and its analogues are potent [2-(1H-imidazol-4-yl)-ethylamino]-cholestan-3β-ol (called inhibitors of ChEH and their treatment leads to the DDA; Figure 1B) induced tumour cell re-differentiation at accumulation of 5,6-ECs in cells [16]. 5,6-ECs exist as two nanomolar concentrations in cancer cells of different tissue diastereoisomers: 5,6α-EC and 5,6β-EC [34]. Interestingly, origins [36]. The effects of DDA on the human BC cell 5,6α-EC was shown to mediate the BC cell re-differentiation line MCF-7 and the human melanoma cell line SKMEL- induced by Tam [16]. Substances bearing epoxide are often 28 were then studied. Treatment of MCF-7 cells with DDA
prone to spontaneous reaction with nucleophiles, however triggered the arrest of cells in the G0–G1-phase of the cell 5,6-EC are exceptions and remain unreactive at ambient cycle. DDA modified cell morphology and cells became temperatures due to the localization of the epoxide ring flattened with increased granulosity. Oil red O staining of on the steroid backbone [34,35]. Under catalytic conditions, cells revealed the accumulation of vesicles containing neutral 5,6α-EC can react stereoselectively with nucleophiles such as lipids. Biochemical analysis showed that these neutral lipids ethanolamine or mercaptoethanol to give a single conjugation were triacylglycerides (TG; Figure 3A). Additionally, DDA product [34,35]. The identification of this stereoselective induced the expression of milk fat globulin, one of the transformation was important in the discovery of DDA as it major proteins found in milk [8,9,36]. Thus, together these provided scientists with a new possible metabolic pathway data showed that DDA induced MCF-7 cell differentiation centred on 5,6α-EC transformation [34]. Interestingly, and activated the lactation function of the original breast conjugation of 5,6α-EC with histamine (HA) and polyamines epithelial cells from lactating ducts. However, perhaps the has also been reported [36]. For each amine, a single product most exciting observation was that DDA appeared to be at was obtained [8,36] that resulted from the trans diaxial least five times more efficient at inducing MCF-7 cell re- ring opening of the epoxide by the primary amine at C6 differentiation compared with a range of other compounds, (Figure 2). Since D8D7I and DHCR7, the two subunits of the including Tam. When tested on SKMEL-28 cells, DDA ChEH, had been reported to be able to control mammalian induced morphological changes, from spindle to dendritic developmental programmes [37], it was postulated that morphology. Ultrastructure analysis of cells by electron