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.

Fitter Mitochondria Are Associated With Radioresistance in Human Head and Neck SQD9 Cancer Cells

“…As previously reported for both HPV-positive and HPVnegative HNSCC cancer cells (Cruz-Gregorio et al, 2019), the different types of metabolic adaptations affecting glycolysis, respiration, glutaminolysis, lipid metabolism and autophagy all converge to protect cells from irradiation by reducing redox stress and/or to accelerate cell repair by accelerating biosynthesis and energy production. We therefore logically expected that enhanced OXPHOS in SQD9-res cells would generate more ATP, more ROS basally activating redox defenses (mitohormesis) and would be a marker of superior mitochondrial integrity compared to SQD9-wt cells.…”

“…While hypoxia causes microenvironmental radioresistance, there is sensibly less yet increasing information about metabolic influences on intrinsic radiosensitivity that would be independent of hypoxia. In a recent review, Cruz-Gregorio et al (2019) highlighted that reprogramming energy metabolism is critical for the induction of radioresistance in head and neck cancer. For example, accelerating the rate of the pentose phosphate pathway (PPP) in Warburg-phenotype Herpes virus (HPV)negative HNSCC cells can increase the production of NADPH that fuels antioxidant enzymes (Williams et al, 2014;Chen et al, 2018;Cruz-Gregorio et al, 2018).…”

mTOR-Mediated Antioxidant Activation in Solid Tumor Radioresistance

“…However, in various solid tumors, because antioxidant mechanisms are activated at higher levels than in normal cells, tumor cells can be more tolerant to excessive ROS levels than normal cells [77]. NRF2-dependent antioxidant enzymes such as SOD, glutathione peroxidase (GPX), glutathione reductase (GSR), peroxiredoxin (PRX), and thioredoxin reductase (TXNRD) are upregulated in tumor cells, and high expression of these proteins is associated with poor prognosis in tumor patients (Table 1) [78][79][80][81][82][83]. Mitochondrial SOD2 was shown to be highly expressed in ovarian cancer patients and contribute to antitumor therapy resistance [84].…”

Emerging therapeutic approaches for canine sarcomas: Pushing the boundaries beyond the conventional

“…The glycolytic intermediates are then diverted toward the synthesis of nucleotides, amino acids, and lipids to generate the biomass needed for uncontrolled cell proliferation . Tumour cells reprogram their energy metabolism to promote cell proliferation and tumour growth, and this ability is intimately linked to hypoxia, mitochondrial physiology, oxidative stress (OS) and autophagy, which can affect and be affected by response to chemotherapy, immunotherapy, and RT . There is abundant interest in developing novel cancer therapies that exploit these aberrant metabolic traits .…”

“…194 Tumour cells reprogram their energy metabolism to promote cell proliferation and tumour growth, and this ability is intimately linked to hypoxia, mitochondrial physiology, oxidative stress (OS) and autophagy, which can affect and be affected by response to chemotherapy, immunotherapy, and RT. 195,196 There is abundant interest in developing novel cancer therapies that exploit these aberrant metabolic traits. [197][198][199] Although drugs that target glycolytic enzymes, such as hexokinase, pyruvate kinase isozyme M2, and lactate dehydrogenase have been evaluated in preclinical studies, 199,200 clinical success has been limited, and drugs targeting glycolysis have not yet been approved as anticancer agents.…”