Treatment resistance analysis reveals GLUT-1-mediated glucose uptake as a major target of synthetic rocaglates in cancer cells

• Verfasst von: Sieber-Frank, Julia [VerfasserIn]
• Verfasst von: Stark, Hans-Jürgen [VerfasserIn]
• Verfasst von: Kalteis, Martin Simon [VerfasserIn]
• Verfasst von: Prigge, Elena-Sophie [VerfasserIn]
• Verfasst von: Köhler, Richard [VerfasserIn]
• Verfasst von: Andresen, Carolin [VerfasserIn]
• Verfasst von: Henkel, Thomas [VerfasserIn]
• Verfasst von: Casari, Georg [VerfasserIn]
• Verfasst von: Schubert, Tobias [VerfasserIn]
• Verfasst von: Fischl, Wolfgang [VerfasserIn]
• Verfasst von: Li-Weber, Min [VerfasserIn]
• Verfasst von: Krammer, Peter H. [VerfasserIn]
• Verfasst von: Knebel Doeberitz, Magnus von [VerfasserIn]
• Verfasst von: Kopitz, Jürgen [VerfasserIn]
• Verfasst von: Kloor, Matthias [VerfasserIn]
• Verfasst von: Ahadova, Aysel [VerfasserIn]
• Titel: Treatment resistance analysis reveals GLUT-1-mediated glucose uptake as a major target of synthetic rocaglates in cancer cells
• Verf.angabe: Julia Sieber-Frank, Hans-Jürgen Stark, Simon Kalteis, Elena-Sophie Prigge, Richard Köhler, Carolin Andresen, Thomas Henkel, Georg Casari, Tobias Schubert, Wolfgang Fischl, Min Li-Weber, Peter H. Krammer, Magnus von Knebel Doeberitz, Jürgen Kopitz, Matthias Kloor, Aysel Ahadova
• Jahr: 2021
• Umfang: 16 S.
• Fussnoten: Gesehen am 05.12.2022
• Titel Quelle: Enthalten in: Cancer medicine
• Ort Quelle: Hoboken, NJ : Wiley, 2012
• Jahr Quelle: 2021
• Band/Heft Quelle: 10(2021), 19, Seite 6807-6822
• ISSN Quelle: 2045-7634
• DOI: doi:10.1002/cam4.4212
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: cancer biology
• Sach-SW: colorectal cancer
• Sach-SW: drug design
• Sach-SW: metabolic studies
• Sach-SW: molecular biology
• K10plus-PPN: 1824426917
• K10plus-PPN:
  Universitätsbibliothek
• Lokale URL UB: Zum Volltext

Abstract

Rocaglates are natural compounds that have been extensively studied for their ability to inhibit translation initiation. Rocaglates represent promising drug candidates for tumor treatment due to their growth-inhibitory effects on neoplastic cells. In contrast to natural rocaglates, synthetic analogues of rocaglates have been less comprehensively characterized, but were also shown to have similar effects on the process of protein translation. Here, we demonstrate an enhanced growth-inhibitory effect of synthetic rocaglates when combined with glucose anti-metabolite 2-deoxy-D-glucose (2DG) in different cancer cell lines. Moreover, we unravel a new aspect in the mechanism of action of synthetic rocaglates involving reduction of glucose uptake mediated by downregulation or abrogation of glucose transporter GLUT-1 expression. Importantly, cells with genetically induced resistance to synthetic rocaglates showed substantially less pronounced treatment effect on glucose metabolism and did not demonstrate GLUT-1 downregulation, pointing at the crucial role of this mechanism for the anti-tumor activity of the synthetic rocaglates. Transcriptome profiling revealed glycolysis as one of the major pathways differentially regulated in sensitive and resistant cells. Analysis of synthetic rocaglate efficacy in a 3D tissue context with a co-culture of tumor and normal cells demonstrated a selective effect on tumor cells and substantiated the mechanistic observations obtained in cancer cell lines. Increased glucose uptake and metabolism is a universal feature across different tumor types. Therefore, targeting this feature by synthetic rocaglates could represent a promising direction for exploitation of rocaglates in novel anti-tumor therapies.