Blocking LDHA glycolytic pathway sensitizes glioblastoma cells to radiation and temozolomide

Koukourakis, Michael I.; Tsolou, Avgi; Pouliliou, Stamatia; Lamprou, Ioannis; Papadopoulou, Maria V.; Ilemosoglou, Maria; Kostoglou, Georgia; Ananiadou, Dimitra; Sivridis, Efthimios; Giatromanolaki, Alexandra

doi:10.1016/j.bbrc.2017.07.138

Cited by 38 publications

(32 citation statements)

References 27 publications

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“…Inhibition of LDHA (41) or HK2 (39) has been shown to sensitize GB cells to radiotherapy and we have shown that c-Myc and glycolytic enzyme expression are correlated with the radioresistance of the cell lines in vitro. Therefore, imaging with hyperpolarized [1-13 C]pyruvate could potentially be used clinically to target increased radiotherapy dose to radioresistant tumors or specific regions of tumors, that is, regions that display increased lactate labeling.…”

Section: Discussionmentioning

confidence: 74%

“…Expression of HK2 and LDHA have been negatively correlated with radiosensitivity (39,41), suggesting that metabolic imaging with hyperpolarized [1-13 C]pyruvate could be used to target increased radiotherapy dose to areas of radioresistance. We investigated this by comparing the effects of irradiation on GB4 and GB1 cells.…”

Section: Inhibition Of C-myc Expression Increased Radiosensitivity Inmentioning

confidence: 99%

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Metabolic Imaging Detects Low Levels of Glycolytic Activity That Vary with Levels of c-Myc Expression in Patient-Derived Xenograft Models of Glioblastoma

et al. 2018

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C MRI of hyperpolarized [1-C]pyruvate metabolism has been used in oncology to detect disease, investigate disease progression, and monitor response to treatment with a view to guiding treatment in individual patients. This technique has translated to the clinic with initial studies in prostate cancer. Here, we use the technique to investigate its potential uses in patients with glioblastoma (GB). We assessed the metabolism of hyperpolarized [1-C]pyruvate in an orthotopically implanted cell line model (U87) of GB and in patient-derived tumors, where these were produced by orthotopic implantation of cells derived from different patients. Lactate labeling was higher in the U87 tumor when compared with patient-derived tumors, which displayed intertumoral heterogeneity, reflecting the intra- and intertumoral heterogeneity in the patients' tumors from which they were derived. Labeling in some patient-derived tumors could be observed before their appearance in morphologic images, whereas in other tumors it was not significantly greater than the surrounding brain. Increased lactate labeling in tumors correlated with c-Myc-driven expression of hexokinase 2, lactate dehydrogenase A, and the monocarboxylate transporters and was accompanied by increased radioresistance. Because c-Myc expression correlates with glioma grade, this study demonstrates that imaging with hyperpolarized [1-C]pyruvate could be used clinically with patients with GB to determine disease prognosis, to detect early responses to drugs that modulate c-Myc expression, and to select tumors, and regions of tumors for increased radiotherapy dose. Metabolic imaging with hyperpolarized [1-C]pyruvate detects low levels of c-Myc-driven glycolysis in patient-derived glioblastoma models, which, when translated to the clinic, could be used to detect occult disease, determine disease prognosis, and target radiotherapy. .

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Section: Discussionmentioning

confidence: 74%

Section: Inhibition Of C-myc Expression Increased Radiosensitivity Inmentioning

confidence: 99%

Metabolic Imaging Detects Low Levels of Glycolytic Activity That Vary with Levels of c-Myc Expression in Patient-Derived Xenograft Models of Glioblastoma

et al. 2018

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“…It was reported that LDHA is upregulated in human tumors, including glioblastoma [ 249 , 250 , 251 ]. The Warburg effect, which is the anaerobic metabolism by tumor cells even under well-oxygenated conditions, has been suggested to be an adaptive mechanism to maintain the biosynthetic requirements of uncontrolled proliferation [ 252 ].…”

Section: Molecular Species Selectivity Of Pabpmentioning

confidence: 99%

New Era of Diacylglycerol Kinase, Phosphatidic Acid and Phosphatidic Acid-Binding Protein

Sakane

Hoshino

Murakami

2020

IJMS

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Diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DG) to generate phosphatidic acid (PA). Mammalian DGK consists of ten isozymes (α–κ) and governs a wide range of physiological and pathological events, including immune responses, neuronal networking, bipolar disorder, obsessive-compulsive disorder, fragile X syndrome, cancer, and type 2 diabetes. DG and PA comprise diverse molecular species that have different acyl chains at the sn-1 and sn-2 positions. Because the DGK activity is essential for phosphatidylinositol turnover, which exclusively produces 1-stearoyl-2-arachidonoyl-DG, it has been generally thought that all DGK isozymes utilize the DG species derived from the turnover. However, it was recently revealed that DGK isozymes, except for DGKε, phosphorylate diverse DG species, which are not derived from phosphatidylinositol turnover. In addition, various PA-binding proteins (PABPs), which have different selectivities for PA species, were recently found. These results suggest that DGK–PA–PABP axes can potentially construct a large and complex signaling network and play physiologically and pathologically important roles in addition to DGK-dependent attenuation of DG–DG-binding protein axes. For example, 1-stearoyl-2-docosahexaenoyl-PA produced by DGKδ interacts with and activates Praja-1, the E3 ubiquitin ligase acting on the serotonin transporter, which is a target of drugs for obsessive-compulsive and major depressive disorders, in the brain. This article reviews recent research progress on PA species produced by DGK isozymes, the selective binding of PABPs to PA species and a phosphatidylinositol turnover-independent DG supply pathway.

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“…R406 alleviates the severity of autoimmune arthritis in mice and provides clinical benefit in patients with rheumatoid arthritis 28 ,29 . Administration of R406 also demonstrates efficacy for autoantibody-induced thrombocytopenia in animal models, and autoimmune thrombocytopenic purpura in humans 30 . In addition, deactivation of Syk signaling by R406 not only induces apoptosis in chronic lymphocytic leukemia cells but also inhibits protective stroma signals 31 .…”

Section: Discussionmentioning

confidence: 95%

R406 elicits anti-Warburg effect via Syk-dependent and -independent mechanisms to trigger apoptosis in glioma stem cells

et al. 2019

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Given that glioma stem cells (GSCs) play a critical role in the initiation and chemoresistance in glioblastoma multiforme (GBM), targeting GSCs is an attractive strategy to treat GBM. Utilizing an anti-cancer compound library, we identified R406, the active metabolite of a FDA-approved Syk inhibitor for immune thrombocytopenia (ITP), with remarkable cytotoxicity against GSCs but not normal neural stem cells. R406 significantly inhibited neurosphere formation and triggered apoptosis in GSCs. R406 induced a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS) and subsequently production of excess ROS in GSCs. R406 also diminished tumor growth and efficiently sensitized gliomas to temozolomide in GSC-initiating xenograft mouse models. Mechanistically, the anti-GSC effect of R406 was due to the disruption of Syk/PI3K signaling in Syk-positive GSCs and PI3K/Akt pathway in Syk-negative GSCs respectively. Overall, these findings not only identify R406 as a promising GSC-targeting agent but also reveal the important role of Syk and PI3K pathways in the regulation of energy metabolism in GSCs.

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Blocking LDHA glycolytic pathway sensitizes glioblastoma cells to radiation and temozolomide

Cited by 38 publications

References 27 publications

Metabolic Imaging Detects Low Levels of Glycolytic Activity That Vary with Levels of c-Myc Expression in Patient-Derived Xenograft Models of Glioblastoma

Metabolic Imaging Detects Low Levels of Glycolytic Activity That Vary with Levels of c-Myc Expression in Patient-Derived Xenograft Models of Glioblastoma

New Era of Diacylglycerol Kinase, Phosphatidic Acid and Phosphatidic Acid-Binding Protein

R406 elicits anti-Warburg effect via Syk-dependent and -independent mechanisms to trigger apoptosis in glioma stem cells

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