Lactate dehydrogenases promote glioblastoma growth and invasion via a metabolic symbiosis

Abstract

Lactate is a central metabolite in brain physiology but also contributes to tumor development. Glioblastoma (GB) is the most common and malignant primary brain tumor in adults, recognized by angiogenic and invasive growth, in addition to its altered metabolism. We show herein that lactate fuels GB anaplerosis by replenishing the tricarboxylic acid (TCA) cycle in absence of glucose. Lactate dehydrogenases (LDHA and LDHB), which we found spatially expressed in GB tissues, catalyze the interconversion of pyruvate and lactate. However, ablation of both LDH isoforms, but not only one, led to a reduction in tumor growth and an increase in mouse survival. Comparative transcriptomics and metabolomics revealed metabolic rewiring involving high oxidative phosphorylation (OXPHOS) in the LDHA/B KO group which sensitized tumors to cranial irradiation, thus improving mouse survival. When mice were treated with the antiepileptic drug stiripentol, which targets LDH activity, tumor growth decreased. Our findings unveil the complex metabolic network in which both LDHA and LDHB are integrated and show that the combined inhibition of LDHA and LDHB strongly sensitizes GB to therapy.

Salvianolic acid A diminishes LDHA‐driven aerobic glycolysis to restrain myofibroblasts activation and cardiac fibrosis via blocking Akt/GSK‐3β/HIF‐1α axis

“…Upon being recognized by the promoter region of the Ldha gene locus, transcription factors (TFs) (Sukonina et al, 2019), such as hypoxia‐inducible factor‐1 (HIF‐1) (Koukourakis et al, 2003; Semenza et al, 1996), stimulate the expression of Ldha , subsequently leading to the reprogramming of glucose metabolism. Inhibiting LDHA expression may reduce the invasive and metastatic potential of cancer cells by decreasing their proliferation ability and reversing their resistance to chemotherapy (Guyon et al, 2022); however, whether manipulating LDHA can produce beneficial impact on cardiac fibrosis is still unclear. Also, whether and how LDHA is modulated in cardiac fibroblasts in response to fibrotic stimuli remains poorly characterized.…”

Inhibition of adaptive therapy tolerance in cancer: is triplet mitochondrial targeting the key?

“…However, recent studies indicate that malignant brain tumors might also be particularly dependent on mitochondrial mechanisms. A recent elegant example of this was a study by Gyon and collaborators where they demonstrated an important role for mitochondrial adaptation in response to radiation therapy in glioblastoma (GB) [ 13 ]. Production of lactate, an end‐product of mitochondrial glycolysis and an important survival factor for GB cells, is catalyzed by lactate dehydrogenase A and B (LDHA and LDHB) proteins.…”

“…Production of lactate, an end‐product of mitochondrial glycolysis and an important survival factor for GB cells, is catalyzed by lactate dehydrogenase A and B (LDHA and LDHB) proteins. The authors demonstrated that in glioblastoma tissue, LDHA and LDHB are spatially differentially expressed and only a few cells expressed both isoforms [ 13 ]. Functionally, lactate production was only inhibited by co‐targeting of both LDHA and B isoforms indicating that in the absence of one isoform, the other isoform can compensate for its activity.…”

“…Further, highlighting the selective impact of different aspects of mitochondrial metabolism in determining therapy sensitivity, double LDHA and LDHB inhibition resulted in an increase in OXPHOS activity, but in this context, high OXPHOS translated into radiation therapy sensitivity of glioblastoma cells. In an intracranial tumor model, triplet mitochondrial targeting by a combination of genetic LDHA and LDHB inhibition with irradiation had a superior impact on mouse survival [ 13 ]. Our own lab's contribution to uncovering the role of mitochondria in cancer therapy tolerance also comes from studies of brain tumor cells.…”

“…Collectively these studies strongly indicate mitochondrial adaptation as an important mechanism behind nongenetic drug tolerance [ 3 , 7 , 8 , 10 , 11 , 13 , 15 ]. Although the combination strategies used across these studies are seemingly different, they do share certain aspects that might be key for their superior activity over the doublet or monotherapies.…”