ArticleThe Journal of biological chemistry2016
Mechanistic Target of Rapamycin (mTOR) Inhibition Synergizes with Reduced Internal Ribosome Entry Site (IRES)-mediated Translation of Cyclin D1 and c-MYC mRNAs to Treat Glioblastoma.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 50 citations in OpenAlex.
- Translated Circular RNAs in Glioblastoma: Emerging Regulators of Tumor Progression, Molecular Heterogeneity and Therapeutic Resistance.International journal of molecular sciences · 2026Review
- Small nucleolar RNAs: the hidden precursors of cancer ribosomes.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2025Review
- The Internal Ribosome Entry Site in Circular RNAs.Advances in experimental medicine and biology · 2025Review
- Readers of RNA Modification in Cancer and Their Anticancer Inhibitors.Biomolecules · 2024Review
- Isoform-Directed Control of c-Myc Functions: Understanding the Balance from Proliferation to Growth Arrest.International journal of molecular sciences · 2023Review
- mCancer letters · 2023Article
- The dark side of mRNA translation and the translation machinery in glioblastoma.Frontiers in cell and developmental biology · 2023Review
- Upregulated Apelin Signaling in Pancreatic Cancer Activates Oncogenic Signaling Pathways to Promote Tumor Development.International journal of molecular sciences · 2022Article
- SFPQ promotes RAS-mutant cancer cell growth by modulating 5'-UTR mediated translational control of CK1α.NAR cancer · 2022Article
- Protein synthesis control in cancer: selectivity and therapeutic targeting.The EMBO journal · 2022Review
- Critical Role for Cap-Independent c-MYC Translation in Progression of Multiple Myeloma.Molecular cancer therapeutics · 2022Article
- hnRNP A1 in RNA metabolism regulation and as a potential therapeutic target.Frontiers in pharmacology · 2022Review
- Chemical and Structural Strategies to Selectively Target mTOR Kinase.ChemMedChem · 2021Review
- mTORC2-mediated direct phosphorylation regulates YAP activity promoting glioblastoma growth and invasive characteristics.Neoplasia (New York, N.Y.) · 2021Article
- CIRP promotes the progression of non-small cell lung cancer through activation of Wnt/β-catenin signaling via CTNNB1.Journal of experimental & clinical cancer research : CR · 2021Article
- Targeting the YAP-TEAD interaction interface for therapeutic intervention in glioblastoma.Journal of neuro-oncology · 2021Article
- The Autism-Related Protein SETD5 Controls Neural Cell Proliferation through Epigenetic Regulation of rDNA Expression.iScience · 2020Article
- Repurposing Potential of Riluzole as an ITAF Inhibitor in mTOR Therapy Resistant Glioblastoma.International journal of molecular sciences · 2020Article
- Repression of PCGF1 Decreases the Proliferation of Glioblastoma Cells in Association with Inactivation of c-Myc Signaling Pathway.OncoTargets and therapy · 2020Article
- Relevance of Translation Initiation in Diffuse Glioma Biology and its Therapeutic Potential.Cells · 2019Review
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Our previous work has demonstrated an intrinsic mRNA-specific protein synthesis salvage pathway operative in glioblastoma (GBM) tumor cells that is resistant to mechanistic target of rapamycin (mTOR) inhibitors. The activation of this internal ribosome entry site (IRES)-dependent mRNA translation initiation pathway results in continued translation of critical transcripts involved in cell cycle progression in the face of global eIF-4E-mediated translation inhibition. Recently we identified compound 11 (C11), a small molecule capable of inhibiting c-MYC IRES translation as a consequence of blocking the interaction of a requisite c-MYC IRES trans-acting factor, heterogeneous nuclear ribonucleoprotein A1, with its IRES. Here we demonstrate that C11 also blocks cyclin D1 IRES-dependent initiation and demonstrates synergistic anti-GBM properties when combined with the mechanistic target of rapamycin kinase inhibitor PP242. The structure-activity relationship of C11 was investigated and resulted in the identification of IRES-J007, which displayed improved IRES-dependent initiation blockade and synergistic anti-GBM effects with PP242. Mechanistic studies with C11 and IRES-J007 revealed binding of the inhibitors within the UP1 fragment of heterogeneous nuclear ribonucleoprotein A1, and docking analysis suggested a small pocket within close proximity to RRM2 as the potential binding site. We further demonstrate that co-therapy with IRES-J007 and PP242 significantly reduces tumor growth of GBM xenografts in mice and that combined inhibitor treatments markedly reduce the mRNA translational state of cyclin D1 and c-MYC transcripts in these tumors. These data support the combined use of IRES-J007 and PP242 to achieve synergistic antitumor responses in GBM.
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