Reprogramming of Energy Metabolism in Response to Radiotherapy in Head and Neck Squamous Cell Carcinoma

Abstract

Head and neck cancer (HNC) is the sixth cause of cancer-related death worldwide. Head and neck squamous cells carcinoma (HNSCC) is the most frequent subtype of HNC. The development of HNSCC is associated to alcohol consumption, smoking or infection by high-risk human Papillomavirus (HR-HPV). Although the incidence of cancers associated with alcohol and tobacco has diminished, HNSCC associated with HR-HPV has significantly increased in recent years. However, HPV-positive HNSCC responds well to treatment, which includes surgery followed by radiation or chemoradiation therapy. Radiation therapy (RT) is based on ionizing radiation (IR) changing cell physiology. IR can directly interact with deoxyribonucleic acid (DNA) or produce reactive oxygen and nitrogen species (RONS), provoking DNA damage. When DNA damage is not repaired, programmed cell death (apoptosis and/or autophagy) is induced. However, cancer cells can acquire resistance to IR avoiding cell death, where reprogramming of energy metabolism has a critical role and is intimately connected with hypoxia, mitochondrial physiology, oxidative stress (OS) and autophagy. This review is focused on the reprogramming of energy metabolism in response to RT in HPV-positive and HPV-negative HNSCC, showing their differences in cellular metabolism management and the probable direction of treatments for each subtype of HNSCC.

Keywords: HNSCC; HR-HPV; metabolic therapy; oxidative stress; radiotherapy; reprogramming of energy metabolism.

Figure 1

Redox state in irradiated HNSCC cells and the effect of HPV oncoproteins. HNSCC cells regulate oxidative stress induced by IR through the overexpression of Nrf2, which in turn activates genes such as catalase, superoxide dismutase (SOD2) and glutathione peroxidase (GPx), associated to antioxidant processes. On the other hand, the HR-HPV E6 protein induce OS, which decreases the GSH/GSSG rate, the levels of catalase and its activity [44]. E6* decreases SOD2 and GPx, provoking OS and consequently, DNA damage [45]. E6/E7 activate Nox2, inducing OS and DNA damage [46]. Therefore, altogether, HPV oncoproteins could sensitize HNSCC cells to radiation therapy. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (Nox2), superoxide dismutase (SOD), heme oxygenase (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione S-transferase (GST), glutathione peroxidase (GPx), catalase (CAT), glutathione (GSH), glutathione disulfide (GSSG), voltage-dependent anion channels (VDAC), peroxynitrite (ONOO⁻), nitric oxide (NO), superoxide anion (O₂^.−), hydrogen peroxide (H₂O₂), hydroxyl radical (OH^.), high-risk human Papillomavirus (HR-HPV), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), antioxidant response elements (ARE), nitric oxide synthase (NOS). The red rays indicate the damage to DNA, protein, carbohydrates and lipids.

Figure 2

Metabolic reprogramming in HNSCC in response to IR. Activation of glycolysis and HIF1 in HPV-negative HNSCC cells induce radioresistance, in comparison to radiosensitive HPV-positive HNSCC cells, where OXPHOS is activated increasing ROS production and OS. In the presences of HPV, COX augments, activating the electron transport chain. Glucose transporter (GLUT), hexokinase (HK), phosphoglucose isomerase (PGI) phosphofructokinase (PFK), hypoxia-inducible factor (HIF), vascular endothelial growth factor (VEFG), pyruvate dehydrogenase kinase (PDK), pyruvate dehydrogenase (PDH), pyruvate dehydrogenase complex (PDC), cytochrome c oxidase (COX), tricarboxylic acid (TCA) cycle, cytochrome (cit), apoptosis protease-activating factor (Apaf), caspase (Cas), lactate dehydrogenase (LDH). The double arrow represents overexpression.