Ergosterol inhibits the proliferation of breast cancer cells by suppressing AKT/GSK-3beta/beta-catenin pathway.
Ergosterol
/ pharmacology
Humans
Glycogen Synthase Kinase 3 beta
/ metabolism
beta Catenin
/ metabolism
Proto-Oncogene Proteins c-akt
/ metabolism
Breast Neoplasms
/ metabolism
Female
Cell Proliferation
/ drug effects
Cell Line, Tumor
MCF-7 Cells
Wnt Signaling Pathway
/ drug effects
Cell Survival
/ drug effects
Phosphorylation
/ drug effects
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
24 Aug 2024
24 Aug 2024
Historique:
received:
27
11
2023
accepted:
19
08
2024
medline:
24
8
2024
pubmed:
24
8
2024
entrez:
23
8
2024
Statut:
epublish
Résumé
Breast cancer is a prevalent malignancy affecting women globally, necessitating effective treatment strategies. This study explores the potential of ergosterol, a bioactive compound found in edible mushrooms, as a candidate for breast cancer treatment. Breast cancer cell lines (MCF-7 and MDA-MB-231) were treated with ergosterol, revealing its ability to inhibit cell viability, induce cell cycle arrest, and suppress spheroid formation. Mechanistically, ergosterol demonstrated significant inhibitory effects on the Wnt/beta-catenin signaling pathway, a critical regulator of cancer progression, by attenuating beta-catenin translocation in the nucleus. This suppression was attributed to the inhibition of AKT/GSK-3beta phosphorylation, leading to decreased beta-catenin stability and activity. Additionally, ergosterol treatment impacted protein synthesis and ubiquitination, potentially contributing to its anti-cancer effects. Moreover, the study revealed alterations in metabolic pathways upon ergosterol treatment, indicating its influence on metabolic processes critical for cancer development. This research sheds light on the multifaceted mechanisms through which ergosterol exerts anti-tumor effects, mainly focusing on Wnt/beta-catenin pathway modulation and metabolic pathway disruption. These findings provide valuable insights into the potential of ergosterol as a therapeutic candidate for breast cancer treatment, warranting further investigation and clinical application.
Identifiants
pubmed: 39179606
doi: 10.1038/s41598-024-70516-1
pii: 10.1038/s41598-024-70516-1
doi:
Substances chimiques
Ergosterol
Z30RAY509F
Glycogen Synthase Kinase 3 beta
EC 2.7.11.1
beta Catenin
0
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
CTNNB1 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
19664Subventions
Organisme : Thailand Science Research and Innovation Fund Chulalongkorn University
ID : HEA663700088
Organisme : the National Research Foundation of Korea
ID : 2018R1A2B2002923 and 2021K2A9A1A2037773
Informations de copyright
© 2024. The Author(s).
Références
Sung, H. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71, 209–249 (2021).
pubmed: 33538338
doi: 10.3322/caac.21660
Lumachi, F., Santeufemia, D. A. & Basso, S. M. Current medical treatment of estrogen receptor-positive breast cancer. World J. Biol. Chem. 6, 231 (2015).
pubmed: 26322178
pmcid: 4549764
doi: 10.4331/wjbc.v6.i3.231
Hortobagyi, G. N. Treatment of breast cancer. New Engl. J. Med. 339, 974–984 (1998).
pubmed: 9753714
doi: 10.1056/NEJM199810013391407
Howard, F. M. & Olopade, O. I. Epidemiology of triple-negative breast cancer: A review. Cancer J. 27, 8–16 (2021).
pubmed: 33475288
doi: 10.1097/PPO.0000000000000500
Shapiro, C. L. & Recht, A. Side effects of adjuvant treatment of breast cancer. New Engl. J. Med. 344, 1997–2008 (2001).
pubmed: 11430330
doi: 10.1056/NEJM200106283442607
Hong, D. et al. Epithelial-to-mesenchymal transition and cancer stem cells contribute to breast cancer heterogeneity. J. Cell. Physiol. 233, 9136–9144 (2018).
pubmed: 29968906
pmcid: 6185773
doi: 10.1002/jcp.26847
Geyer, F. C. et al. β-Catenin pathway activation in breast cancer is associated with triple-negative phenotype but not with CTNNB1 mutation. Modern Pathol. 24, 209–231 (2011).
doi: 10.1038/modpathol.2010.205
Ram Makena, M. et al. Wnt/β-catenin signaling: The culprit in pancreatic carcinogenesis and therapeutic resistance. Int. J. Mol. Sci. 20, 4242 (2019).
pubmed: 31480221
pmcid: 6747343
doi: 10.3390/ijms20174242
Zhang, Y. & Wang, X. Targeting the Wnt/β-catenin signaling pathway in cancer. J. Hematol. Oncol. 13, 1–16 (2020).
doi: 10.1186/s13045-020-00990-3
Wang, Z. et al. Clinical implications of β-catenin protein expression in breast cancer. Int. J. Clin. Exp. Pathol. 8, 14989 (2015).
pubmed: 26823833
pmcid: 4713619
Huang, M., Lu, J.-J. & Ding, J. Natural products in cancer therapy: Past, present and future. Nat. Prod. Bioprospect. 11, 5–13 (2021).
pubmed: 33389713
pmcid: 7933288
doi: 10.1007/s13659-020-00293-7
Dupont, S. et al. Antioxidant properties of ergosterol and its role in yeast resistance to oxidation. Antioxidants 10, 1024 (2021).
pubmed: 34202105
pmcid: 8300696
doi: 10.3390/antiox10071024
Xiong, M. et al. Antidiabetic activity of ergosterol from Pleurotus ostreatus in KK-Ay mice with spontaneous type 2 diabetes mellitus. Mol. Nutr. Food Res. 62, 1700444 (2018).
doi: 10.1002/mnfr.201700444
Mbambo, B., Odhav, B. & Mohanlall, V. Antifungal activity of stigmasterol, sitosterol and ergosterol from Bulbine natalensis Baker (Asphodelaceae). J. Med. Plants Res. 6, 5135–5141 (2012).
doi: 10.5897/JMPR12.151
Sillapachaiyaporn, C., Nilkhet, S., Ung, A. T. & Chuchawankul, S. Anti-HIV-1 protease activity of the crude extracts and isolated compounds from Auricularia polytricha. BMC Complement. Altern. Med. 19, 1–10 (2019).
doi: 10.1186/s12906-019-2766-3
Sillapachaiyaporn, C., Mongkolpobsin, K., Chuchawankul, S., Tencomnao, T. & Baek, S. J. Neuroprotective effects of ergosterol against TNF-α-induced HT-22 hippocampal cell injury. Biomed. Pharmacother. 154, 113596 (2022).
pubmed: 36030584
doi: 10.1016/j.biopha.2022.113596
Takaku, T., Kimura, Y. & Okuda, H. Isolation of an antitumor compound from Agaricus blazei Murill and its mechanism of action. J. Nutr. 131, 1409–1413 (2001).
pubmed: 11340091
doi: 10.1093/jn/131.5.1409
Chen, S. et al. Anti-tumor and anti-angiogenic ergosterols from Ganoderma lucidum. Front. Chem. 5, 85 (2017).
pubmed: 29164102
pmcid: 5670154
doi: 10.3389/fchem.2017.00085
Wu, H.-Y. et al. Ergosterol peroxide from marine fungus Phoma sp. induces ROS-dependent apoptosis and autophagy in human lung adenocarcinoma cells. Sci. Rep. 8, 17956 (2018).
pubmed: 30560887
pmcid: 6298985
doi: 10.1038/s41598-018-36411-2
Ikarashi, N. et al. A mechanism by which ergosterol inhibits the promotion of bladder carcinogenesis in rats. Biomedicines 8, 180 (2020).
pubmed: 32605038
pmcid: 7400612
doi: 10.3390/biomedicines8070180
Martínez-Montemayor, M. M. et al. Identification of biologically active Ganoderma lucidum compounds and synthesis of improved derivatives that confer anti-cancer activities in vitro. Front. Pharmacol. 10, 115 (2019).
pubmed: 30837881
pmcid: 6389703
doi: 10.3389/fphar.2019.00115
Li, X. et al. Ergosterol purified from medicinal mushroom Amauroderma rude inhibits cancer growth in vitro and in vivo by up-regulating multiple tumor suppressors. Oncotarget 6, 17832 (2015).
pubmed: 26098777
pmcid: 4627349
doi: 10.18632/oncotarget.4026
Barth, A. I., Stewart, D. B. & Nelson, W. J. T cell factor-activated transcription is not sufficient to induce anchorage-independent growth of epithelial cells expressing mutant β-catenin. Proc. Natl. Acad. Sci. 96, 4947–4952 (1999).
pubmed: 10220399
pmcid: 21797
doi: 10.1073/pnas.96.9.4947
Fang, D. et al. Phosphorylation of β-catenin by AKT promotes β-catenin transcriptional activity. J. Biol. Chem. 282, 11221–11229 (2007).
pubmed: 17287208
doi: 10.1074/jbc.M611871200
Pai, S. G. et al. Wnt/beta-catenin pathway: Modulating anticancer immune response. J. Hematol. Oncol. 10, 1–12 (2017).
doi: 10.1186/s13045-017-0471-6
Wang, L., Zhang, S. & Wang, X. The metabolic mechanisms of breast cancer metastasis. Front. Oncol. 10, 602416 (2021).
pubmed: 33489906
pmcid: 7817624
doi: 10.3389/fonc.2020.602416
Sanderson, J. T. The steroid hormone biosynthesis pathway as a target for endocrine-disrupting chemicals. Toxicol. Sci. 94, 3–21 (2006).
pubmed: 16807284
doi: 10.1093/toxsci/kfl051
Ogretmen, B. Sphingolipid metabolism in cancer signalling and therapy. Nat. Rev. Cancer 18, 33–50 (2018).
pubmed: 29147025
doi: 10.1038/nrc.2017.96
Wang, W., Cui, J., Ma, H., Lu, W. & Huang, J. Targeting pyrimidine metabolism in the era of precision cancer medicine. Front. Oncol. 11, 684961 (2021).
pubmed: 34123854
pmcid: 8194085
doi: 10.3389/fonc.2021.684961
Berdiaki, A. et al. Glycosaminoglycans: Carriers and targets for tailored anti-cancer therapy. Biomolecules 11, 395 (2021).
pubmed: 33800172
pmcid: 8001210
doi: 10.3390/biom11030395
Liu, D. et al. Small molecules from natural products targeting the Wnt/β-catenin pathway as a therapeutic strategy. Biomed. Pharmacother. 117, 108990 (2019).
pubmed: 31226638
doi: 10.1016/j.biopha.2019.108990
Huber, O. et al. Nuclear localization of β-catenin by interaction with transcription factor LEF-1. Mech. Dev. 59, 3–10 (1996).
pubmed: 8892228
doi: 10.1016/0925-4773(96)00597-7
Hagen, T. & Vidal-Puig, A. Characterisation of the phosphorylation of β-catenin at the GSK-3 priming site Ser45. Biochem. Biophys. Res. Commun. 294, 324–328 (2002).
pubmed: 12051714
doi: 10.1016/S0006-291X(02)00485-0
Liu, C. et al. Control of β-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 108, 837–847 (2002).
pubmed: 11955436
doi: 10.1016/S0092-8674(02)00685-2
Shi, J. et al. Deubiquitinase USP47/UBP64E regulates β-catenin ubiquitination and degradation and plays a positive role in Wnt signaling. Mol. Cell. Biol. 35, 3301–3311 (2015).
pubmed: 26169834
pmcid: 4561727
doi: 10.1128/MCB.00373-15
Yang, B. et al. Deubiquitinase USP9X deubiquitinates β-catenin and promotes high grade glioma cell growth. Oncotarget 7, 79515 (2016).
pubmed: 27783990
pmcid: 5346732
doi: 10.18632/oncotarget.12819
Park, H.-B., Kim, J.-W. & Baek, K.-H. Regulation of Wnt signaling through ubiquitination and deubiquitination in cancers. Int. J. Mol. Sci. 21, 3904 (2020).
pubmed: 32486158
pmcid: 7311976
doi: 10.3390/ijms21113904
DeBerardinis, R. J. & Chandel, N. S. Fundamentals of cancer metabolism. Sci. Adv. 2(5), e1600200 (2016).
pubmed: 27386546
pmcid: 4928883
doi: 10.1126/sciadv.1600200
Capper, C. P., Rae, J. M. & Auchus, R. J. The metabolism, analysis, and targeting of steroid hormones in breast and prostate cancer. Hormones Cancer 7, 149–164 (2016).
pubmed: 26969590
pmcid: 4860032
doi: 10.1007/s12672-016-0259-0
Wei, J., Hu, M., Huang, K., Lin, S. & Du, H. Roles of proteoglycans and glycosaminoglycans in cancer development and progression. Int. J. Mol. Sci. 21, 5983 (2020).
pubmed: 32825245
pmcid: 7504257
doi: 10.3390/ijms21175983
Abuetabh, Y. et al. Expression of E-cadherin and β-catenin in two cholangiocarcinoma cell lines (OZ and HuCCT1) with different degree of invasiveness of the primary tumor. Annals Clin. Lab. Sci. 41, 217–223 (2011).
Disoma, C., Zhou, Y., Li, S., Peng, J. & Xia, Z. Wnt/β-catenin signaling in colorectal cancer: Is therapeutic targeting even possible?. Biochimie 195, 39–53 (2022).
pubmed: 35066101
doi: 10.1016/j.biochi.2022.01.009
Xu, X., Zhang, M., Xu, F. & Jiang, S. Wnt signaling in breast cancer: Biological mechanisms, challenges and opportunities. Mol. Cancer 19, 1–35 (2020).
doi: 10.1186/s12943-020-01276-5