Unappreciated Role of LDHA and LDHB to Control Apoptosis and Autophagy in Tumor Cells

Abstract

Tumor cells possess a high metabolic plasticity, which drives them to switch on the anaerobic glycolysis and lactate production when challenged by hypoxia. Among the enzymes mediating this plasticity through bidirectional conversion of pyruvate and lactate, the lactate dehydrogenase A (LDHA) and lactate dehydrogenase B (LDHB), are indicated. LDHA has a higher affinity for pyruvate, preferentially converting pyruvate to lactate, and NADH to NAD+ in anaerobic conditions, whereas LDHB possess a higher affinity for lactate, preferentially converting lactate to pyruvate, and NAD+ to NADH, when oxygen is abundant. Apart from the undisputed role of LDHA and LDHB in tumor cell metabolism and adaptation to unfavorable environmental or cellular conditions, these enzymes participate in the regulation of cell death. This review presents the latest progress made in this area on the roles of LDHA and LDHB in apoptosis and autophagy of tumor cells. Several examples of how LDHA and LDHB impact on these processes, as well as possible molecular mechanisms, will be discussed in this article. The information included in this review points to the legitimacy of modulating LDHA and/or LDHB to target tumor cells in the context of human and veterinary medicine.

Prognostic Significance of Baseline Neutrophil Count and Lactate Dehydrogenase Level in Patients With Esophageal Squamous Cell Cancer Treated With Radiotherapy

“…According to previous studies, an elevated level of LDH isoforms is more common in malignant tumors than normal cells (32). The increased LDH level could promote tumor progression by regulating the tumor metabolism and microenvironment and acts as a poor prognostic indicator for cancer patients (32,33). A meta-analysis investigating the prognostic value of the LDH level in solid tumors showed that a high LDH level is associated with poor survival in melanoma, gastric, lung cancer, prostate, and renal cell carcinomas (34).…”

“…According to previous studies, an elevated level of LDH isoforms is more common in malignant tumors than normal cells (32). The increased LDH level could promote tumor progression by regulating the tumor metabolism and microenvironment and acts as a poor prognostic indicator for cancer patients (32,33).…”

Modified DNA Aptamers for C-Reactive Protein and Lactate Dehydrogenase-5 with Sub-Nanomolar Affinities

“…Lactate dehydrogenase (LDH) is a detectable enzyme in the cytoplasm of nearly all cells in the human body, and its extracellular presence is associated with cell necrosis and tissue destruction, since it becomes extracellular due to cell death [27,28]. LDH is an enzyme whose activity is routinely measured clinically, and it has subtypes ranging from LDH-1 to LDH-5 [29]. The isoenzyme profile of LDH activity is different in the saliva and in the blood: while LDH-5 is dominant in the former, LDH-1 is dominant in the latter [30].…”

<p>FAM46B Promotes Apoptosis and Inhibits Glycolysis of Prostate Cancer Through Inhibition of the MYC-LDHA Axis</p>

“…Indeed, LDHA is dysregulated in several cancers including pancreatic cancer, 14,15 breast cancer, 16,17 and glioma, 18 plays a role in the aggressiveness of gastric cancer; 19 and controls apoptosis in some cancer types. 20 Expression of LDHA is speculated to be regulated by a few known factors, including fibroblast growth factor receptor, 21 cyclin G2, 22 FLF4, 23 FOXM1, 24 or through a welldefined MYC-LDHA pathway; 14,25,26 however, there are little data beyond these, particularly in regards to upstream initiators.…”