Seliger, Corinna and Leukel, Petra and Moeckel, Sylvia and Jachnik, Birgit and Lottaz, Claudio and Kreutz, Marina and Brawanski, Alexander and Proescholdt, Martin and Bogdahn, Ulrich and Bosserhoff, Anja-Katrin and Vollmann-Zwerenz, Arabel and Hau, Peter (2013) Lactate-Modulated Induction of THBS-1 Activates Transforming Growth Factor (TGF)-beta2 and Migration of Glioma Cells In Vitro. PLOS ONE, 8 (11): e78935. ISSN 1932-6203,
Full text not available from this repository. (Request a copy)Abstract
Background: An important phenomenon observed in glioma metabolism is increased aerobic glycolysis in tumor cells, which is generally referred to as the Warburg effect. Transforming growth factor (TGF)-beta2, which we previously showed to be induced by lactic acid, is a key pathophysiological factor in glioblastoma, leading to increased invasion and severe local immunosuppression after proteolytic cleavage from its latency associated peptide. In this study we tested the hypothesis, that lactate regulates TGF-beta2 expression and glioma cell migration via induction of Thrombospondin-1 (THBS-1), a TGF-beta activating protein. Methods: Lactate levels were reduced by knockdown of LDH-A using specific small interfering RNA (siRNA) and competitive inhibition of LDH-A by sodium oxamate. Knockdown of THBS-1 was performed using specific siRNA. Western Blot, qRT-PCR, and ELISA were used to investigate expression levels of LDH-A, LDH-B, TGF-beta2 and THBS-1. Migration of cells was examined by Spheroid, Scratch and Boyden Chamber assays. Results: Knockdown of LDH-A with subsequent decrease of lactate concentration leads to reduced levels of THBS-1 and TGF-beta2 in glioma cells. Lactate addition increases THBS-1 protein, leading to increased activation of TGF-beta2. Inhibition of THBS-1 reduces TGF-beta2 protein and migration of glioma cells. Addition of synthetic THBS-1 can rescue reduced TGF-beta2 protein levels and glioma cell migration in siLDH-A treated cells. Conclusion: We define a regulatory cascade between lactate, THBS-1 and TGF-beta2, leading to enhanced migration of glioma cells. Our results demonstrate a specific interaction between tumor metabolism and migration and provide a better understanding of the mechanisms underlying glioma cell invasion.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CANCER STEM-CELLS; LATENT TGF-BETA; MATRIX METALLOPROTEINASE-2; THROMBOSPONDIN-1; EXPRESSION; GLIOBLASTOMA; MALIGNANCY; PROTEINS; MOTILITY; BINDING; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) Medicine > Lehrstuhl für Neurochirurgie Medicine > Lehrstuhl für Neurologie Medicine > Lehrstuhl für Pathologie Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Statistische Bioinformatik (Prof. Spang) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 26 Mar 2020 11:55 |
| Last Modified: | 26 Mar 2020 11:55 |
| URI: | https://pred.uni-regensburg.de/id/eprint/15763 |
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