Fatty Acid Synthase As Interacting Anticancer Target of the Terpenoid Myrianthic Acid Disclosed by MS-Based Proteomics Approaches

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2024 Jun 19

PMID 38892106

Authors

Alessandra Capuano

Gilda DUrso

Erica Gazzillo

Gianluigi Lauro

Maria Giovanna Chini

Maria Valeria Dauria

Maria Grazia Ferraro

Federica Iazzetti

Carlo Irace

Giuseppe Bifulco

Agostino Casapullo

Affiliations

Soon will be listed here.

Abstract

This research focuses on the target deconvolution of the natural compound myrianthic acid, a triterpenoid characterized by an ursane skeleton isolated from the roots of and from Nutt. (Onagraceae), using MS-based chemical proteomic techniques. Application of drug affinity responsive target stability (DARTS) and targeted-limited proteolysis coupled to mass spectrometry (t-LiP-MS) led to the identification of the enzyme fatty acid synthase (FAS) as an interesting macromolecular counterpart of myrianthic acid. This result, confirmed by comparison with the natural ursolic acid, was thoroughly investigated and validated in silico by molecular docking, which gave a precise picture of the interactions in the MA/FAS complex. Moreover, biological assays showcased the inhibitory activity of myrianthic acid against the FAS enzyme, most likely related to its antiproliferative activity towards tumor cells. Given the significance of FAS in specific pathologies, especially cancer, the myrianthic acid structural moieties could serve as a promising reference point to start the potential development of innovative approaches in therapy.

References

Iqbal J, Abbasi B, Ahmad R, Mahmood T, Kanwal S, Ali B . Ursolic acid a promising candidate in the therapeutics of breast cancer: Current status and future implications. Biomed Pharmacother. 2018; 108:752-756. DOI: 10.1016/j.biopha.2018.09.096. View

Zhang J, Lei J, Wei G, Chen H, Ma C, Jiang H . Natural fatty acid synthase inhibitors as potent therapeutic agents for cancers: A review. Pharm Biol. 2016; 54(9):1919-25. DOI: 10.3109/13880209.2015.1113995. View

Lomenick B, Jung G, Wohlschlegel J, Huang J . Target identification using drug affinity responsive target stability (DARTS). Curr Protoc Chem Biol. 2012; 3(4):163-180. PMC: 3251962. DOI: 10.1002/9780470559277.ch110180. View

Lin Y, Wang C, Chang H, Chu F, Hsu Y, Cheng W . Ursolic Acid, a Novel Liver X Receptor α (LXRα) Antagonist Inhibiting Ligand-Induced Nonalcoholic Fatty Liver and Drug-Induced Lipogenesis. J Agric Food Chem. 2018; 66(44):11647-11662. DOI: 10.1021/acs.jafc.8b04116. View

Piccolo M, Misso G, Ferraro M, Riccardi C, Capuozzo A, Zarone M . Exploring cellular uptake, accumulation and mechanism of action of a cationic Ru-based nanosystem in human preclinical models of breast cancer. Sci Rep. 2019; 9(1):7006. PMC: 6505035. DOI: 10.1038/s41598-019-43411-3. View

Laszczyk M . Pentacyclic triterpenes of the lupane, oleanane and ursane group as tools in cancer therapy. Planta Med. 2009; 75(15):1549-60. DOI: 10.1055/s-0029-1186102. View

Picotti P, Aebersold R . Selected reaction monitoring-based proteomics: workflows, potential, pitfalls and future directions. Nat Methods. 2012; 9(6):555-66. DOI: 10.1038/nmeth.2015. View

Pappenberger G, Benz J, Gsell B, Hennig M, Ruf A, Stihle M . Structure of the human fatty acid synthase KS-MAT didomain as a framework for inhibitor design. J Mol Biol. 2010; 397(2):508-19. DOI: 10.1016/j.jmb.2010.01.066. View

Irace C, Misso G, Capuozzo A, Piccolo M, Riccardi C, Luchini A . Antiproliferative effects of ruthenium-based nucleolipidic nanoaggregates in human models of breast cancer in vitro: insights into their mode of action. Sci Rep. 2017; 7:45236. PMC: 5368645. DOI: 10.1038/srep45236. View

10.

Fhu C, Ali A . Fatty Acid Synthase: An Emerging Target in Cancer. Molecules. 2020; 25(17). PMC: 7504791. DOI: 10.3390/molecules25173935. View

11.

Vanauberg D, Schulz C, Lefebvre T . Involvement of the pro-oncogenic enzyme fatty acid synthase in the hallmarks of cancer: a promising target in anti-cancer therapies. Oncogenesis. 2023; 12(1):16. PMC: 10024702. DOI: 10.1038/s41389-023-00460-8. View

12.

Xiao Y, Yang Y, Xiong H, Dong G . The implications of FASN in immune cell biology and related diseases. Cell Death Dis. 2024; 15(1):88. PMC: 10810964. DOI: 10.1038/s41419-024-06463-6. View

13.

Schcolnik-Cabrera A, Chavez-Blanco A, Dominguez-Gomez G, Taja-Chayeb L, Morales-Barcenas R, Trejo-Becerril C . Orlistat as a FASN inhibitor and multitargeted agent for cancer therapy. Expert Opin Investig Drugs. 2018; 27(5):475-489. DOI: 10.1080/13543784.2018.1471132. View

14.

Kazakova O, Soica C, Babaev M, Petrova A, Khusnutdinova E, Poptsov A . 3-Pyridinylidene Derivatives of Chemically Modified Lupane and Ursane Triterpenes as Promising Anticancer Agents by Targeting Apoptosis. Int J Mol Sci. 2021; 22(19). PMC: 8509773. DOI: 10.3390/ijms221910695. View

15.

Alqahtani A, Hamid K, Kam A, Wong K, Abdelhak Z, Razmovski-Naumovski V . The pentacyclic triterpenoids in herbal medicines and their pharmacological activities in diabetes and diabetic complications. Curr Med Chem. 2012; 20(7):908-31. View

16.

Lomenick B, Olsen R, Huang J . Identification of direct protein targets of small molecules. ACS Chem Biol. 2010; 6(1):34-46. PMC: 3031183. DOI: 10.1021/cb100294v. View

17.

Uhlen M, Fagerberg L, Hallstrom B, Lindskog C, Oksvold P, Mardinoglu A . Proteomics. Tissue-based map of the human proteome. Science. 2015; 347(6220):1260419. DOI: 10.1126/science.1260419. View

18.

Khwaza V, Oyedeji O, Aderibigbe B . Ursolic Acid-Based Derivatives as Potential Anti-Cancer Agents: An Update. Int J Mol Sci. 2020; 21(16). PMC: 7460570. DOI: 10.3390/ijms21165920. View

19.

Raida M . Drug target deconvolution by chemical proteomics. Curr Opin Chem Biol. 2011; 15(4):570-5. DOI: 10.1016/j.cbpa.2011.06.016. View

20.

Fontana A, Polverino de Laureto P, Spolaore B, Frare E, Picotti P, Zambonin M . Probing protein structure by limited proteolysis. Acta Biochim Pol. 2004; 51(2):299-321. View