Modulators of Redox Metabolism in Head and Neck Cancer

Abstract

Significance: Head and neck squamous cell cancer (HNSCC) is a complex disease characterized by high genetic and metabolic heterogeneity. Radiation therapy (RT) alone or combined with systemic chemotherapy is widely used for treatment of HNSCC as definitive treatment or as adjuvant treatment after surgery. Antibodies against epidermal growth factor receptor are used in definitive or palliative treatment. Recent Advances: Emerging targeted therapies against other proteins of interest as well as programmed cell death protein 1 and programmed death-ligand 1 immunotherapies are being explored in clinical trials.

Critical issues: The disease heterogeneity, invasiveness, and resistance to standard of care RT or chemoradiation therapy continue to constitute significant roadblocks for treatment and patients' quality of life (QOL) despite improvements in treatment modality and the emergence of new therapies over the past two decades.

Future directions: As reviewed here, alterations in redox metabolism occur at all stages of HNSCC management, providing opportunities for improved prevention, early detection, response to therapies, and QOL. Bioinformatics and computational systems biology approaches are key to integrate redox effects with multiomics data from cells and clinical specimens and to identify redox modifiers or modifiable target proteins to achieve improved clinical outcomes. Antioxid. Redox Signal.

Keywords: HNSCC; head and neck; oxidative stress; redox; squamous cancer.

FIG. 1.

Stages during HNSCC development and their relationship with altered redox homeostasis. ROS underlies cancer etiology, progression, and response to treatment, and is used for diagnosis and improving patient's QOL. CRT, chemoradiation therapy; CT, computed tomography; EGFR, epidermal growth factor receptor; HNSCC, head and neck squamous cell cancer; HPV, human papillomavirus; MRI, magnetic resonance imaging; NAC, N-acetylcysteine; PET, positron emission tomography; QOL, quality of life; ROS, reactive oxygen species; SOD, superoxide dismutase. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 2.

EGFR signaling pathways. Activation of EGFR by ligand binding leads to a myriad of downstream signaling pathways (e.g., PI3K/Akt pathway, Ras/Raf/MEK/ERK pathway, JAK/STAT pathway, and NF-κB pathway) that ultimately drive tumor cell growth, angiogenesis, invasion, etc. Note that PI3K is required for membrane recruitment of Rac, a NOX subunit, and the subsequent ROS production. EGFR-targeted monoclonal antibodies block ligand binding to the extracellular domain of EGFR. EGFR-targeted TKIs inhibit the catalytic domain of EGFR. Mechanisms for resistance to EGFR-targeted therapies include EGFR oxidation/mutation with increased/constitutive activity, activation of redundant kinase signaling pathways (e.g., c-MET and HER2), and EGFR-independent activation of downstream pathways (e.g., PI3K/Akt). Bold borders indicate redox-regulated proteins. Akt, protein kinase B; c-MET, tyrosine-protein kinase Met; EGF, epidermal growth factor; ERK, extracellular signal-regulated kinase; Grb2, growth factor receptor-bound protein 2; HER2, human epidermal growth factor receptor 2; IKK, IκB kinase; JAK, Janus kinase; MEK, mitogen-activated protein kinase kinase; mTOR, mechanistic target of rapamycin; NADPH, nicotinamide adenine dinucleotide phosphate; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NOX, NADPH oxidase; PI3K, phosphatidylinositide 3-kinase; PRX, peroxiredoxin; PTEN, phosphatase and tensin homologue; Rac, Ras-related C3 botulinum toxin substrate; SHP2, tyrosine-protein phosphatase nonreceptor type 11; STAT, signal transducer and activator of transcription factor; TKI, tyrosine kinase inhibitor. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 3.

Redox mechanisms for drug resistance. IR and/or intrinsic ROS generate an oxidative tumor microenvironment, which can modify the anticancer drug, rendering it less effective (e.g., erlotinib and its oxidized forms shown in the bottom) and the protein target itself (e.g., EGFR). IR and/or intrinsic ROS also affect tumor signaling, cell metabolism, and epigenetics in a cyclic way resulting in changes in the cellular phenotype, which, in turn, would impact tumor progression and response to therapies. EMT, epithelial-mesenchymal transition; IR, ionizing radiation; MET, mesenchymal-epithelial transition. To see this illustration in color, the reader is referred to the online version of this article at www.liebertpub.com/ars.

FIG. 4.

Exploiting NQO1 bioactivatable drugs for radiosensitization of HNSCCs. NQO1 metabolizes β-lapachone to an unstable hydroquinone (quinol) that spontaneously and rapidly converts back to its original compound using two oxygenation steps and creating two molecules of superoxides, which then damage DNA and cause cell death via programmed necrosis (NAD⁺-Keresis). This process is dependent on calcium release, and pretreatment with a specific calcium chelator BAPTA-AM inhibits NQO1-dependent cell death. AP, apurinic/apyrimidinic; BER, base excision repair; DSB, double-strand break; ER, endoplasmic reticulum; NQO1, quinone oxidoreductase 1; PARP, poly ADP ribose polymerase; SSB, single-strand break. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 5.

Mechanisms of PD-1 and CTLA-4 in immunosuppression. In the priming phase, dendritic cells present antigens to T cells via the interaction of MHC and TCR. B7 binding to CD28 generates a costimulatory signal. CTLA-4, upregulated shortly after activation, negatively regulates T cell activation by outcompeting CD28 for binding to B7. In the effector phase, PD-1 is expressed on activated T cells and binds to PD-L1/2 expressed on tumor cells, sending an inhibitory signal to T cells. Anti-CTLA-4 antibodies (e.g., ipilimumab) and anti-PD-1/PD-L1 antibodies (e.g., nivolumab and pembrolizumab) enhance T cell function by turning off the inhibitory signal. CD, cluster of differentiation; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; MHC, major histocompatibility complex; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; TCR, T cell receptor. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 6.

Mechanisms for radiation therapy. IR causes water radiolysis generating ROS that leads to DNA damage, lipid peroxidation, and protein oxidation. IR also directly damages DNA. ROS can oxidize specific protein cysteine residue to unstable sulfenic acid, which can be reversed back to thiol through mixed-disulfide formation. Further oxidation of sulfenic acid results in irreversible conversion to sulfinic and sulfonic acids. Upregulation of antioxidant systems and DNA damage responses can restore redox homeostasis and macromolecule integrity, underlying major mechanisms for radiation resistance. GPX, glutathione peroxidase; TRX, thioredoxin. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 7.

Cellular sources of ROS and the antioxidant systems. Two major cellular sources of ROS are produced by mitochondria ETC and NOX. In ETC, leaky electrons from complexes I and III reduce oxygen to superoxide. Cytosolic superoxide, generated by the NOX complex or transported by VDAC from mitochondria ETC, can be dismutated by Cu/ZnSOD to H₂O₂ and oxygen. Cytosolic H₂O₂ is then dismutated to water and oxygen by CAT, PRX/TRX/TR, or GPX/GSH/GR system using the reducing power of NADPH. Similarly, mitochondrial superoxide can be degraded by MnSOD and then PRX3 and GPX1 resided in the mitochondria. CAT, catalase; ETC, electron transport chain; GR, glutathione reductase; GSH, glutathione; GSSG, oxidized glutathione; MPC, mitochondria pyruvate carrier; TR, thioredoxin reductase; VDAC, voltage-dependent anion channel. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 8.

Mechanisms for cisplatin therapy. Cisplatin enters the cell through passive diffusion or active transport via CTR1/2 or OCT2. Binding of cisplatin to DNA results in platinum adducts, causing kinking of the DNA and inhibiting DNA transcription and cell proliferation until DNA damage is repaired or the cell dies. Resistance to cisplatin treatment can be due to (i) decreased influx and increased efflux, (ii) increased DNA repair, and (iii) neutralization with protein thiols. ABC, ATP-binding cassette; ATP, adenosine triphosphate; CTR, copper transporter protein; GST, glutathione S-transferase; OCT, organic cation transporter. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 9.

Key concepts connecting patient metabolic state and tumor redox state to tumor progression and response to treatment. Patients' diet and lifestyle underlie many aspects of HNSCC etiology by affecting energy metabolism and, therefore, genomic stability. At the same time, patient metabolic state affects tumor redox state, and together they drive tumor progression and response to treatment. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars