دورية أكاديمية
أعرض في EDS

Developing a Tanshinone IIA Memetic by Targeting MIOS to Regulate mTORC1 and Autophagy in Glioblastoma.

التفاصيل البيبلوغرافية
العنوان: Developing a Tanshinone IIA Memetic by Targeting MIOS to Regulate mTORC1 and Autophagy in Glioblastoma.
المؤلفون: Shinhmar S; Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham TW20 0EX, UK., Schaf J; Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham TW20 0EX, UK., Lloyd Jones K; Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham TW20 0EX, UK., Pardo OE; Division of Cancer, Department of Surgery and Cancer, Imperial College London, London SW7 2AZ, UK., Beesley P; Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham TW20 0EX, UK., Williams RSB; Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham TW20 0EX, UK.
المصدر: International journal of molecular sciences [Int J Mol Sci] 2024 Jun 14; Vol. 25 (12). Date of Electronic Publication: 2024 Jun 14.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Basel, Switzerland : MDPI, [2000-
مواضيع طبية MeSH: Glioblastoma*/drug therapy , Glioblastoma*/metabolism , Glioblastoma*/pathology , Abietanes*/pharmacology , Mechanistic Target of Rapamycin Complex 1*/metabolism , Mechanistic Target of Rapamycin Complex 1*/antagonists & inhibitors , Autophagy*/drug effects , Dictyostelium*/drug effects , Dictyostelium*/metabolism, Humans ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Nuclear Proteins/metabolism ; Nuclear Proteins/genetics ; Nuclear Proteins/antagonists & inhibitors ; Sestrins
مستخلص: Tanshinone IIA (T2A) is a bioactive compound that provides promise in the treatment of glioblastoma multiforme (GBM), with a range of molecular mechanisms including the inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) and the induction of autophagy. Recently, T2A has been demonstrated to function through sestrin 2 (SESN) to inhibit mTORC1 activity, but its possible impact on autophagy through this pathway has not been investigated. Here, the model system Dictyostelium discoideum and GBM cell lines were employed to investigate the cellular role of T2A in regulating SESN to inhibit mTORC1 and activate autophagy through a GATOR2 component MIOS. In D. discoideum , T2A treatment induced autophagy and inhibited mTORC1 activity, with both effects lost upon the ablation of SESN (sesn - ) or MIOS (mios - ). We further investigated the targeting of MIOS to reproduce this effect of T2A, where computational analysis identified 25 novel compounds predicted to strongly bind the human MIOS protein, with one compound (MIOS inhibitor 3; Mi3) reducing cell proliferation in two GBM cells. Furthermore, Mi3 specificity was demonstrated through the loss of potency in the D. discoideum mios - cells regarding cell proliferation and the induction of autophagy. In GBM cells, Mi3 treatment also reduced mTORC1 activity and induced autophagy. Thus, a potential T2A mimetic showing the inhibition of mTORC1 and induction of autophagy in GBM cells was identified.
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معلومات مُعتمدة: N/A BBSRC DTP studentship
فهرسة مساهمة: Keywords: Dictyostelium discoideum; GATOR2; MIOS; autophagy; cancer; drug discovery; glioblastoma; mTORC1; sestrin; tanshinone IIA
المشرفين على المادة: 0 (Abietanes)
EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
03UUH3J385 (tanshinone)
0 (SESN2 protein, human)
0 (Nuclear Proteins)
0 (Sestrins)
تواريخ الأحداث: Date Created: 20240627 Date Completed: 20240627 Latest Revision: 20240722
رمز التحديث: 20240722
مُعرف محوري في PubMed: PMC11204349
DOI: 10.3390/ijms25126586
PMID: 38928292
قاعدة البيانات: MEDLINE
الوصف
تدمد:1422-0067
DOI:10.3390/ijms25126586