Suppression of lactate dehydrogenase A compromises tumor progression by downregulation of the Warburg effect in glioblastoma

Abstract

Reprogrammed glucose metabolism is an emerging hallmark of cancer cells, which show a unique metabolic phenotype known as the Warburg effect. Lactate dehydrogenase A (LDHA), a key enzyme in the glycolytic process, executes the final step by conversion of lactate into pyruvate. However, little is known about the roles of LDHA in human glioblastoma (GBM). In this study, we aimed to determine the effects of LDHA and elucidate related underlying mechanisms. Data derived from Oncomine database showed that LDHA is commonly upregulated in GBM tissues in comparison with corresponding normal controls. Silencing of LDHA expression resulted in reduced glycolysis, decreased cell growth, increased cell apoptosis, and attenuated invasive ability. In the presence of 2-deoxyglucose, a glycolysis inhibitor, the oncogenic activities of LDHA were completely blocked. These findings provide evidence of the cellular functions of LDHA in the progression of GBM and suggest that LDHA might act as a potential therapeutic target for GBM treatment.

Silencing LDHA inhibits proliferation, induces apoptosis and increases chemosensitivity to temozolomide in glioma cells

“…Increased levels of LDHA have been reported in several types of tumors (11,(13)(14)(15), and its expression levels have been correlated with clinical stages in breast cancer, renal cell carcinoma and prostate cancer; these reports further support that therapies targeting LDHA may provide useful strategies for controlling cancer progression. Moreover, previous reports using data from the Oncomine database showed that the mRNA levels of LDHA were up-regulated in GBM compared to those in matched normal tissues; these results prompted us to determine the correlation between LDHA expression levels and glioma malignancy (16). Consistent with previous studies, our results showed that there was a significant positive correlation between LDHA expression levels and GBM clinical stages.…”

“…Although the abnormal expression of LDHA has been reported in several cancers (10)(11)(12)(13)(14)(15), little is known about the expression pattern of LDHA and its underlying roles in GBM. Previous reports using data from the Oncomine database showed that the mRNA levels of LDHA were up-regulated in GBM compared to matched tissues (16); these finding prompted us to examine the underlying role of LDHA in glioma malignancy.…”

Sexual dimorphism in glioma glycolysis underlies sex differences in survival

“…Lactate dehydrogenase A (LDHA) that converts pyruvate to lactate (and an important component of poor prognostic metabolic subtype 3) and the MCTs that transport lactate and/or pyruvate (SLC16A3 and SLC16A8) across the plasma membrane were part of this signature. LDHA overexpression in solid tumors including gliomas has been implicated in tumor progression, immune evasion, and reduced survival in solid tumors including gliomas (41)(42)(43)(44). Intriguingly, there is evidence of a sexual dimorphism in LDHA expression in both serum and tissue samples in healthy animals (45,46).…”

LDHA is a direct target of miR‐30d‐5p and contributes to aggressive progression of gallbladder carcinoma

“…4 During aerobic glycolysis, lactate dehydrogenase-A (LDHA) preferentially metabolizes pyruvate to lactate. 4 During aerobic glycolysis, lactate dehydrogenase-A (LDHA) preferentially metabolizes pyruvate to lactate.…”