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

**Authors:** Camila M. Scudeler, Keila Samantha da Silva, Rafaela V. N. Silva, Adilha M. R. Micheletti, Karen B. Ribeiro, Juliana Reis Machado, Régia C. P. Lira

PMC · DOI: 10.1155/bri/1853546 · Biochemistry Research International · 2026-02-16

## TL;DR

This review explores how NADPH-related enzymes, detected via immunohistochemistry, may serve as biomarkers for cancer progression and prognosis.

## Contribution

The paper highlights specific NADPH-related enzymes as potential biomarkers for cancer aggressiveness using immunohistochemistry.

## Key findings

- G6PD, malic enzymes, and MTHFD2 show consistent immunolabeling results linked to cancer progression.
- ALDH1, GDH, and DHFR require further study to determine their potential as cancer biomarkers.
- IHC is a promising tool for assessing NADPH-related enzymes in tumor prognosis.

## Abstract

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.

## Linked entities

- **Genes:** G6PD (glucose-6-phosphate dehydrogenase) [NCBI Gene 2539], MTHFD2 (methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 2, methenyltetrahydrofolate cyclohydrolase) [NCBI Gene 10797], ALDH1A1 (aldehyde dehydrogenase 1 family member A1) [NCBI Gene 216], GLUD1 (glutamate dehydrogenase 1) [NCBI Gene 2746], DHFR (dihydrofolate reductase) [NCBI Gene 1719]
- **Diseases:** cancer (MONDO:0004992)

## Full-text entities

- **Genes:** MTHFD2 (methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 2, methenyltetrahydrofolate cyclohydrolase) [NCBI Gene 10797] {aka NMDMC}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, ALDH1L1 (aldehyde dehydrogenase 1 family member L1) [NCBI Gene 10840] {aka 10-FTHFDH, 10-fTHF, FDH, FTHFD}, NOX4 (NADPH oxidase 4) [NCBI Gene 50507] {aka KOX, KOX-1, RENOX}, FOS (Fos proto-oncogene, AP-1 transcription factor subunit) [NCBI Gene 2353] {aka AP-1, C-FOS, p55}, Mapk8 (mitogen-activated protein kinase 8) [NCBI Gene 26419] {aka JNK, JNK1, Prkm8, SAPK1}, PHGDH (phosphoglycerate dehydrogenase) [NCBI Gene 26227] {aka 3-PGDH, 3PGDH, HEL-S-113, NLS, NLS1, PDG}, TYMS (thymidylate synthetase) [NCBI Gene 7298] {aka DKCD, HST422, TMS, TS}, G6pd2 (glucose-6-phosphate dehydrogenase 2) [NCBI Gene 14380] {aka G6pdx-ps1, Gpd-2, Gpd2}, ME3 (malic enzyme 3) [NCBI Gene 10873] {aka NADP-ME}, p53-ps (Wistar clone pR53P1 p53 pseudogene) [NCBI Gene 301300], PGD (phosphogluconate dehydrogenase) [NCBI Gene 5226] {aka 6PGD}, ERBB2 (erb-b2 receptor tyrosine kinase 2) [NCBI Gene 2064] {aka CD340, HER-2, HER-2/neu, HER2, MLN 19, MLN-19}, Me1 (malic enzyme 1) [NCBI Gene 24552] {aka MOD1}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, GLUD2 (glutamate dehydrogenase 2) [NCBI Gene 2747] {aka GDH2, GLUDP1}, MMP2 (matrix metallopeptidase 2) [NCBI Gene 4313] {aka CLG4, CLG4A, MMP-2, MMP-II, MONA, TBE-1}, MTHFD1 (methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1) [NCBI Gene 4522] {aka CIMAH, MTHFC, MTHFD}, MTHFD2L (methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 2 like) [NCBI Gene 441024], TP53 (tumor protein p53) [NCBI Gene 7157] {aka BCC7, BMFS5, LFS1, P53, TRP53}, NADK2 (NAD kinase 2, mitochondrial) [NCBI Gene 133686] {aka C5orf33, DECRD, MNADK, NADKD1}, DHFR (dihydrofolate reductase) [NCBI Gene 1719] {aka DHFR1, DYR}, TENM1 (teneurin transmembrane protein 1) [NCBI Gene 10178] {aka ODZ1, ODZ3, TEN-M1, TEN1, TNM, TNM1}, ALDH1L2 (aldehyde dehydrogenase 1 family member L2) [NCBI Gene 160428] {aka mtFDH}, ALDH1A1 (aldehyde dehydrogenase 1 family member A1) [NCBI Gene 216] {aka ALDC, ALDH-E1, ALDH1, ALDH11, HEL-9, HEL-S-53e}, ME1 (malic enzyme 1) [NCBI Gene 4199] {aka HUMNDME, MES}, AFP (alpha fetoprotein) [NCBI Gene 174] {aka AFPD, FETA, HPAFP}, MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475] {aka FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS}, GLUD1 (glutamate dehydrogenase 1) [NCBI Gene 2746] {aka GDH, GDH1, GLUD, hGDH1}, Me2 (malic enzyme 2) [NCBI Gene 307270], ME2 (malic enzyme 2) [NCBI Gene 4200] {aka ODS1}, NNT (nicotinamide nucleotide transhydrogenase) [NCBI Gene 23530] {aka GCCD4}, NADK (NAD kinase) [NCBI Gene 65220] {aka NADK1, dJ283E3.1}, IDH1 (isocitrate dehydrogenase (NADP(+)) 1) [NCBI Gene 3417] {aka HEL-216, HEL-S-26, IDCD, IDH, IDP, IDPC}, PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}, G6PD (glucose-6-phosphate dehydrogenase) [NCBI Gene 2539] {aka CNSHA1, G6PD1}, MTHFD1L (methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1 like) [NCBI Gene 25902] {aka FTHFSDC1, MTC1THFS, dJ292B18.2}, IDH2 (isocitrate dehydrogenase (NADP(+)) 2) [NCBI Gene 3418] {aka D2HGA2, ICD-M, IDH, IDH-2, IDHM, IDP}
- **Diseases:** node (MESH:D012804), melanoma (MESH:D008545), osteosarcoma (MESH:D012516), pancreatic cancer (MESH:D010190), small- and squamous-cell lung cancer (MESH:D055752), cervical cancer (MESH:D002583), Cancer (MESH:D009369), adenocarcinoma (MESH:D000230), lung cancer (MESH:D008175), fibrosarcoma (MESH:D005354), intraepithelial neoplasia (MESH:D002578), adrenal carcinoma (MESH:D000310), obesity (MESH:D009765), breast, gastric, and oral cancers (MESH:D013274), pediatric rhabdomyosarcoma (MESH:D012208), oral lesions (MESH:D009059), gallbladder carcinoma (MESH:D005706), carcinogenesis (MESH:D063646), oral cancer (MESH:D009062), erythroleukemia (MESH:D004915), mesenchymal tumors (MESH:C535700), renal cancer (MESH:D007680), nasopharyngeal cancer (MESH:D009303), Hypoxia (MESH:D000860), salivary gland tumors (MESH:D012468), oral squamous cell carcinoma (MESH:D000077195), squamous cell carcinoma (MESH:D002294), metastases (MESH:D009362), colorectal cancer (MESH:D015179), leukemia (MESH:D007938), preneoplastic lesions (MESH:D011230), parasitosis (MESH:D063726), lung, breast, esophageal, ovarian, and renal cancers (MESH:D061325), death (MESH:D003643), acute lymphocytic leukemia (MESH:D054198), central nervous system tumors (MESH:D016543), cytotoxicity (MESH:D064420), nodal (MESH:D013611), breast and laryngeal tumors (MESH:D001943), lymph node metastasis (MESH:D008207), bacterial infections (MESH:D001424), ME Types 1 and 2 (MESH:D003924), lung, pancreatic, and ovarian cancers (MESH:D010051), hepatocellular and esophageal cancer (MESH:D004938), hepatocellular carcinoma (MESH:D006528), invasive tumors (MESH:D009361), brain tumors (MESH:D001932), chondrosarcoma (MESH:D002813), RCC (MESH:D002292), bladder tumors (MESH:D001749), glioblastoma (MESH:D005909)
- **Chemicals:** pyruvate (MESH:D019289), methionine (MESH:D008715), GTP (MESH:D006160), ammonia (MESH:D000641), acid (MESH:D000143), formate (MESH:C030544), 6-phosphogluconolactone (MESH:C114004), G6P (MESH:D019298), lactate (MESH:D019344), Pentose phosphate (MESH:D010428), dihydrofolate (MESH:C010920), Tricarboxylic acid (MESH:D014233), carbon (MESH:D002244), ADP (MESH:D000244), MTX (MESH:D008727), tyrosine (MESH:D014443), leucine (MESH:D007930), nucleotide (MESH:D009711), glutamate (MESH:D018698), GDP (MESH:D006153), 10-Formyl-tetrahydrofolate (MESH:C010161), ribulose-5-phosphate (MESH:C031524), malate (MESH:C030298), 5,10-Methylene-tetrahydrofolate (MESH:C013123), pemetrexed (MESH:D000068437), one (-), 6-Aminonicotinamide (MESH:D015120), alpha-KG (MESH:D007656), NAD(P) + (MESH:D009249), fatty acid (MESH:D005227), CoA (MESH:D003065), TCA (MESH:D014238), glutamine (MESH:D005973), THF (MESH:C030371), glutathione (MESH:D005978), PX-12 (MESH:C412893), ATP (MESH:D000255), purine (MESH:C030985), lipid (MESH:D008055), DHEA (MESH:D003687), alcohol (MESH:D000438), NADH (MESH:D009243), folate (MESH:D005492), ROS (MESH:D017382), glucose (MESH:D005947)
- **Species:** Mus musculus (house mouse, species) [taxon 10090], Hepatitis B virus (no rank) [taxon 10407], Rattus norvegicus (brown rat, species) [taxon 10116], Homo sapiens (human, species) [taxon 9606]
- **Mutations:** G6P
- **Cell lines:** HPV18 — Homo sapiens (Human), Transformed cell line (CVCL_4843), HeLa — Homo sapiens (Human), Human papillomavirus-related endocervical adenocarcinoma, Cancer cell line (CVCL_0030)

## Full text

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## Figures

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## References

105 references — full list in the complete paper: https://tomesphere.com/paper/PMC12910181/full.md

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Source: https://tomesphere.com/paper/PMC12910181