The Critical Role of Tetrahydrobiopterin (BH4) Metabolism in Modulating Radiosensitivity: BH4/NOS Axis as an Angel or a Devil

Abstract

Ionizing radiation and radioactive materials have been widely used in industry, medicine, science and military. The efficacy of radiotherapy and adverse effects of normal tissues are closed related to cellular radiosensitivity. Molecular mechanisms underlying radiosensitivity are of significance to tumor cell radiosensitization as well as normal tissue radioprotection. 5,6,7,8-Tetrahydrobiopterin (BH4) is an essential cofactor for nitric oxide synthases (NOS) and aromatic amino acid hydroxylases, and its biosynthesis involves de novo biosynthesis and a pterin salvage pathway. In this review we overview the role of BH4 metabolism in modulating radiosensitivity. BH4 homeostasis determines the role of NOS, affecting the production of nitric oxide (NO) and oxygen free radicals. Under conditions of oxidative stress, such as UV-radiation and ionizing radiation, BH4 availability is diminished due to its oxidation, which subsequently leads to NOS uncoupling and generation of highly oxidative free radicals. On the other hand, BH4/NOS axis facilitates vascular normalization, a process by which antiangiogenic therapy corrects structural and functional flaws of tumor blood vessels, which enhances radiotherapy efficacy. Therefore, BH4/NOS axis may serve as an angel or a devil in regulating cellular radiosensitivity. Finally, we will address future perspectives, not only from the standpoint of perceived advances in treatment, but also from the potential mechanisms. These advances have demonstrated that it is possible to modulate cellular radiosensitivity through BH4 metabolism.

Keywords: 5; 6; 7; 8-tetrahydrobiopterin (BH4); nitric oxide (NO); nitric oxide synthase (NOS); radiation; radiosensitivity.

Figure 1

Enzyme cofactor activity of BH4. BH4 is an essential cofactor for multiple enzymes, including three aromatic amino acid hydroxylases (PAH, TH and TPH) and nitric oxide synthases (NOSs). All three NOSs need BH4 to produce NO. Generally, these enzymes combine the oxidation of L-arginine with the reduction of molecular oxygen to form NO and L-citrulline. BH4 is also the cofactor activity of three aromatic amino acid hydroxylases, which leads to the synthesis of neurotransmitters and prevents the accumulation of phenylalanine.

Figure 2

Pathways for the biosynthesis of BH4. The de novo pathway (left) is synthesized from GTP to BH4 in three steps. GCH1 is the rate-limiting enzyme in BH4 de novo biosynthesis. The salvage pathway (right) produces BH4 from its oxidized form, starting with sepiapterin in two steps, which is essential to convert exogenous sepiapterin into BH4.

Figure 3

Schematic representation of BH4 metabolism in radiosensitivity. Radiation oxidates BH4, which results in NOS uncoupling and augmented radiation-induced secondary ROS, ultimately leading to radiation-induced injuries. While GCH1-mediated BH4 metabolism attenuated radiation-induced ROS production to improve radiation damage.

Figure 4

The expression of BH4 metabolic enzymes in human tumors. The comparison of (A) GCH1, (B) PTPS, (C) SR and (D) DHFR expression in in various tumor tissues and corresponding normal tissues. And BH4 metabolic enzymes generally overexpress in tumor tissues than corresponding normal tissues. *P < 0.05, **P < 0.01 and ***P < 0.001, compared with the normal tissues. Gene expression data are obtained from the Cancer Genome Atlas (TCGA) database (44). BLCA, Bladder urothelial carcinoma; BRCA, Breast invasive carcinoma; CHOL, Cholangiocarcinoma; COAD, Colon adenocarcinoma; ESCA, Esophageal carcinoma; GBM, Glioblastoma multiforme; HNSC, Head and Neck squamous cell carcinoma; KICH, Kidney Chromophobe; KIRC, Kidney renal clear cell carcinoma; KIRP, Kidney renal papillary cell carcinoma; LGG, Brain Lower Grade Glioma; LIHC, Liver hepatocellular carcinoma; LUAD, Lung adenocarcinoma; LUSC, Lung squamous cell carcinoma; PAAD, Pancreatic adenocarcinoma; PRAD, Prostate adenocarcinoma; READ, Rectum adenocarcinoma; STAD, Stomach adenocarcinoma; THCA, Thyroid carcinoma; UCEC, Uterine Corpus Endometrial Carcinoma.

Figure 5

Identified normal tissues or cancer types associated with BH4-mdiated radiosensitivity. Green represents normal tissue, while red represents tumor tissue. Brief description of pathways associated with BH4 are shown.