NADPH‐Related Enzymes and Cancer: Facts and Insights Into the Application of Immunohistochemistry

During tumorigenesis and metastasis, cancer cells initiate antioxidant defense mechanisms to prevent irreversible damage, thereby sustaining tumor growth. The functionality of reactive oxygen species (ROS)-scavenging proteins is dependent on nicotinamide adenine dinucleotide phosphate (NADPH), which is regulated by specific metabolic enzymes, which are described as potential biomarkers of cancer aggressiveness. Immunohistochemistry (IHC) is one of the most accessible and widely utilized techniques to augment the pathological diagnosis of cancer. Hence, this review addresses the protein expression of NADPH-related enzymes, as assessed by IHC, and their associations with human cancer progression factors (overall survival, tumor staging, metastasis, and recurrence). Studies indicate that glucose-6-phosphate dehydrogenase (G6PD), along with malic enzymes and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), represents the most pertinent enzymes examined through IHC concerning cancer aggressiveness. The immunolabeling method produced consistent results for this group of enzymes, which might lead to successful application in predicting tumor prognosis. Other NADPH-related enzymes, such as glutamate dehydrogenase (GDH), aldehyde dehydrogenase 1 (ALDH1), and dihydrofolate reductase (DHFR), deserve more extensive investigation to elucidate their potential as cancer biomarkers via IHC.