The expression of hypoxia-inducible factor-1 in primary brain tumors

Reszeć, Joanna; Rutkowski, Robert; Chyczewski, L

doi:10.3109/00207454.2013.789874

Cited by 14 publications

(15 citation statements)

References 17 publications

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“…HIF1 promotes the transcription of target genes involved in metabolism (including LDHA), angiogenesis and apoptosis, which support cell survival in hypoxic environments. However, HIF1α is also often stabilized in cancers, including brain tumors , by other factors such as overexpression of pyruvate kinase isozymes M2 (PKM2), Ras, proto‐oncogene tyrosine‐protein kinase Src and ErbB2 and constitutive activation of the phosphatidylinositol‐4,5‐bisphosphate 3‐kinase (PI3k), protein kinase B (Akt) or mammalian target of rapamycin (mTOR) pathway . Furthermore, overexpression of HIF1α is associated with LDHA overexpression and a significantly poorer survival in some cancers .…”

Section: Regulation Of Ldha Synthesismentioning

confidence: 99%

The Regulation and Function of Lactate Dehydrogenase A: Therapeutic Potential in Brain Tumor

et al. 2015

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There are over 120 types of brain tumor and approximately 45% of primary brain tumors are gliomas, of which glioblastoma multiforme (GBM) is the most common and aggressive with a median survival rate of 14 months. Despite progress in our knowledge, current therapies are unable to effectively combat primary brain tumors and patient survival remains poor. Tumor metabolism is important to consider in therapeutic approaches and is the focus of numerous research investigations. Lactate dehydrogenase A (LDHA) is a cytosolic enzyme, predominantly involved in anaerobic and aerobic glycolysis (the Warburg effect); however, it has multiple additional functions in non-neoplastic and neoplastic tissues, which are not commonly known or discussed. This review summarizes what is currently known about the function of LDHA and identifies areas that would benefit from further exploration. The current knowledge of the role of LDHA in the brain and its potential as a therapeutic target for brain tumors will also be highlighted. The Warburg effect appears to be universal in tumors, including primary brain tumors, and LDHA (because of its involvement with this process) has been identified as a potential therapeutic target. Currently, there are, however, no suitable LDHA inhibitors available for tumor therapies in the clinic. LACTATE DEHYDROGENASELactate dehydrogenase (LDH) is a tetrameric enzyme, belonging to the 2-hydroxy acid oxidoreductase family, which increases the rate of the simultaneous inter-conversion of pyruvate to lactate and nicotinamide adenine dinucleotide (NAD)H to NAD + by 14 orders of magnitude (10) (Figure 1). The reaction involves the transfer of a hydride ion from NADH to the C2 carbon of pyruvate (99) and is commonly used by cells for anaerobic respiration. There are four LDH genes: LDHA, LDHB, LDHC and LDHD (Figure 2). LDHA, LDHB and LDHC are L isomers, whereas LDHD is a D isomer. The L isomers use or produce L-lactate, which is the major enantiomer found in vertebrates.The human LDHA gene is located on chromosome 11p15.4, the transcribed protein has 332 amino acids, a predicted molecular weight of 37 kDa and 24 splice variants; the human genome also contains several non-transcribed LDHA pseudogenes (32, 126). Evolutionarily, LDHA and LDHB are thought to have arisen from the duplication of a single LDHA-like LDH gene (82). LDHC, a testes-specific gene, is also thought to have evolved in mammals from the duplication of the LDHA gene after the A-B duplication (82).LDHA is also known as the M subunit as it is predominantly found in skeletal muscle, and LDHB is also known as the H subunit as it is predominantly found in the heart. Unlike the other LDH genes, which can form only homotetramers, LDHA and LDHB can form homo-or heterotetramers. There are five isoenzymes of LDH that can be made from the M and H subunits: LDH-1 (4H), LDH-2 (3H, 1M), LDH-3 (2H, 2M), LDH-4 (1H, 3M), and LDH-5 (5M) (Figure 2). LDH-1 and LDH-5 have identical active site regions and only differ in 81 out of 332 amino acid positions, mo...

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Section: Regulation Of Ldha Synthesismentioning

confidence: 99%

The Regulation and Function of Lactate Dehydrogenase A: Therapeutic Potential in Brain Tumor

et al. 2015

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“…Increased surface expression of PD-L1 was previously shown to enhance the efficacy of avelumab-directed ADCC against chordoma, a cancer found in the skull base and spine (14). PD-L1 is upregulated by hypoxia and IFN-γ (32,33), which are associated with advanced grade in meningioma (34). Meningioma cell lines cultured under hypoxia upregulated total PD-L1 protein compared with basal levels ( Figure 3A).…”

Section: Resultsmentioning

confidence: 81%

Efficient ADCC killing of meningioma by avelumab and a high-affinity natural killer cell line, haNK

Giles¹,

Hao²,

Padget³

et al. 2019

JCI Insight

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“…Moreover, loss of TGF-beta and bone morphogenetic protein signaling components and TGF-b type III receptor may contribute to the development and progression of higher grade meningiomas [104]. Moreover, all meningiomas, which progressed from low-to high-grade meningiomas, were HIF-1 positive [105].…”

Section: Meningiomamentioning

confidence: 99%

Innate and Adaptive Immunity Linked to Recognition of Antigens Shared by Neural Crest-Derived Tumors

Donato

Presta

Arcidiacono

et al. 2020

Cancers

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In the adult, many embryologic processes can be co-opted by during cancer progression. The mechanisms of divisions, migration, and the ability to escape immunity recognition linked to specific embryo antigens are also expressed by malignant cells. In particular, cells derived from neural crests (NC) contribute to the development of multiple cell types including melanocytes, craniofacial cartilage, glia, neurons, peripheral and enteric nervous systems, and the adrenal medulla. This plastic performance is due to an accurate program of gene expression orchestrated with cellular/extracellular signals finalized to regulate long-distance migration, proliferation, differentiation, apoptosis, and survival. During neurulation, prior to initiating their migration, NC cells must undergo an epithelial–mesenchymal transition (EMT) in which they alter their actin cytoskeleton, lose their cell–cell junctions, apicobasal polarity, and acquire a motile phenotype. Similarly, during the development of the tumors derived from neural crests, comprising a heterogeneous group of neoplasms (Neural crest-derived tumors (NCDTs)), a group of genes responsible for the EMT pathway is activated. Here, retracing the molecular pathways performed by pluripotent cells at the boundary between neural and non-neural ectoderm in relation to the natural history of NCDT, points of contact or interposition are highlighted to better explain the intricate interplay between cancer cells and the innate and adaptive immune response.

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The expression of hypoxia-inducible factor-1 in primary brain tumors

Cited by 14 publications

References 17 publications

The Regulation and Function of Lactate Dehydrogenase A: Therapeutic Potential in Brain Tumor

The Regulation and Function of Lactate Dehydrogenase A: Therapeutic Potential in Brain Tumor

Efficient ADCC killing of meningioma by avelumab and a high-affinity natural killer cell line, haNK

Innate and Adaptive Immunity Linked to Recognition of Antigens Shared by Neural Crest-Derived Tumors

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