Lactate dehydrogenase A: A key player in carcinogenesis and potential target in cancer therapy

Abstract

Elevated glycolysis remains a universal and primary character of cancer metabolism, which deeply depends on dysregulated metabolic enzymes. Lactate dehydrogenase A (LDHA) facilitates glycolytic process by converting pyruvate to lactate. Numerous researches demonstrate LDHA has an aberrantly high expression in multiple cancers, which is associated with malignant progression. In this review, we summarized LDHA function in cancer research. First, we gave an introduction of structure, location, and basic function of LDHA. Following, we discussed the transcription and activation mode of LDHA. Further, we focused on the function of LDHA in cancer bio‐characteristics. Later, we discussed the clinical practice of LDHA in cancer prevention and treatment. What we discussed gives a precise insight into LDHA especially in cancer research, which will contribute to exploring cancer pathogenesis and its handling measures.

Lactate Beyond a Waste Metabolite: Metabolic Affairs and Signaling in Malignancy

“…As examples, upregulation of LDHA levels in pancreatic and esophageal cancer have been associated with metastasis, tumor stage, tumor recurrence, and patient survival (137). However, LDHA expression in malignant tumor tissues does not correlate consistently with serum LDH levels, which may indicate that these are independent prognostic factors in cancer (138,139). Studies on lactate transporters (MCTs/CD147) are not as solid as for LDH, but also reveal prognostic value ( Table 1) (41).…”

“…LDHA overexpression has been associated with increased cancer aggressiveness and targeting has been tackled both genetically and pharmacologically. There are different types of LDHA inhibitors, including the pyruvate-competitive (e.g., oxamate), the NADH-competitive (e.g., gossypol), the pyruvate and NADH-competitive (N-hydroxyindoles), and the free enzymebinding inhibitors (galloflavin) (138). LDH pharmacological inhibition reduces lactate production, impairs cell proliferation in vitro, and reduces tumor size in vivo, either with LDH inhibitors alone or in combination with other agents (138,141).…”

“…There are different types of LDHA inhibitors, including the pyruvate-competitive (e.g., oxamate), the NADH-competitive (e.g., gossypol), the pyruvate and NADH-competitive (N-hydroxyindoles), and the free enzymebinding inhibitors (galloflavin) (138). LDH pharmacological inhibition reduces lactate production, impairs cell proliferation in vitro, and reduces tumor size in vivo, either with LDH inhibitors alone or in combination with other agents (138,141). Additionally, gossypol has also demonstrated promising results in different clinical trials, being relatively safe and effective in reducing tumor markers (138,142).…”

An Integrated Meta-Analysis of Secretome and Proteome Identify Potential Biomarkers of Pancreatic Ductal Adenocarcinoma

“…Mohammad et al [139] showed that increased expression of LDHA and PKM2 in pancreatic biopsy specimens from patients correlates with poor survival. Studies investigating the LDH expression levels in tumor and serum found that high tissue expression is not entirely consistent with elevated serum levels, indicating that tumor LDHA expression and serum levels are two independent predictors of the disease [140]. In our analysis, LDHA was identified in six secretome studies and only two from the proteome, suggesting that this enzyme may be secreted to perform its functions in tissues distant from the primary tumor focus, exacerbating the tumor progression.…”

Precision-targeted metabolomics method characterizes differential metabolomes in multiple-biological matrixes and cell-mitochondria

“…Specific metabolites are of great biochemical significance. For an example, a high level of lactate in blood can be a sign of liver and kidney diseases even the cancer, therefore the quantification of functional metabolites shows great potential application in disease diagnosis and pathogenesis 19,20 . In our protocol, we used a set of external standards each containing at least five-levels concentration to establish the calibration curves, finally, 84 key metabolites can be absolutely quantitated by the established LC-MS method ( Table 2).…”