Prognostic and therapeutic potential of nuclear receptors in head and neck squamous cell carcinomas

Abstract

Head and neck squamous cell carcinomas are among the most common neoplasms worldwide and characterized by local tumor aggressiveness, high rate of early recurrences, development of metastasis, and second primary cancers. Despite modern therapeutic strategies and sophisticated surgical management, overall survival-rates remained largely unchanged over the last decades. Thus, the need for novel treatment options for this tumor entity is undeniable. A key event in carcinogenesis is the uncontrolled modulation of genetic programs. Nuclear receptors belong to a large superfamily of transcription factors implicated in a broad spectrum of physiological and pathophysiological processes, including cancer. Several nuclear receptors have also been associated with head and neck cancer. This review will summarize their mode of action, prognostic/therapeutic relevance, as well as preclinical and clinical studies currently targeting nuclear receptors in this tumor entity.

Figure 1

Schematic anatomy of the head and neck region. Head and neck cancer includes different types of malignancies that can develop in the mouth, nose and throat.

Figure 2

Domain organization and structural binding modes of NRs. Upper panel: NRs are composed of an N-terminal regulatory domain (activation function 1 = AF1), followed by a DNA-binding domain (DBD), a ligand-binding domain (LBD), and a C-terminal domain (activation function 2 = AF2). Left panel: 3D model illustrating how the DBDs of the RAR/RXR heterodimer (PDB 1DSZ) interact with their target DNA-sequence. Right panel: solid ribbon representation illustrating the LBD of the RAR/RXR heterodimer (PDB 1DKF) complexed with the ligands 9-cis-RA for RXR (PDB 3LBD) and ATRA for RAR (PDB 2LBD). PDB files are taken from the RCBS Protein Data Bank (http://www.pdb.org/).

Figure 3

Simplified model illustrating the two major modes of NR activation. Natural or synthetic ligands diffuse through the cell membrane and bind to cytosolic or nuclear NRs. Ligand binding to cytoplasmic NRs triggers conformational changes resulting in dissociation of heat shock proteins (HSPs) and receptor dimerization, allowing active nuclear import and transactivation by binding to HREs. Other NRs are constitutively nuclear and complexed with corepressors in the absence of ligands. Ligand binding induces conformational changes resulting in the recruitment of coactivators to activate transcription of target genes.

Figure 4

DNA-binding modes of NRs implicated in HNSCC. RAR can heterodimerize with PPARs, which can be activated by lipophilic ligands. Alternatively, RARs are able to heterodimerize with RXRs, which are activated by 9-cis RA. Such heterodimers can bind to specific half-site retinoic acid (RARE) or peroxisome proliferator response elements (PPREs) direct repeats in the DNA of target genes. Estradiol binding induces estrogen receptor homodimerization and binding to palindromic half-site estrogen response element (ERE) inverted repeats. N: Any nucleotide occurring within the specific response element.