Open AccessTreatment resistance analysis reveals GLUT‐1‐mediated glucose uptake as a major target of synthetic rocaglates in cancer cells
Author(s) -
SieberFrank Julia,
Stark HansJürgen,
Kalteis Simon,
Prigge ElenaSophie,
Köhler Richard,
Andresen Carolin,
Henkel Thomas,
Casari Georg,
Schubert Tobias,
Fischl Wolfgang,
LiWeber Min,
Krammer Peter H.,
Knebel Doeberitz Magnus,
Kopitz Jürgen,
Kloor Matthias,
Ahadova Aysel
Publication year - 2021
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.4212
Subject(s) - downregulation and upregulation , transcriptome , cancer cell , cell culture , glucose transporter , glucose uptake , biology , glycolysis , cancer research , carbohydrate metabolism , context (archaeology) , glucose transporter type 1 , metabolite , microbiology and biotechnology , chemistry , biochemistry , metabolism , cancer , gene expression , gene , genetics , glut1 , endocrinology , paleontology , insulin
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.