Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most frequent cancer worldwide. The pregnane X receptor (PXR) is a nuclear receptor regulating several target genes associated with cancer malignancy. We here demonstrated a significant effect of PXR on HNSCC cell growth, as evidenced in PXR knock-down experiments. PXR transcriptional activity is more importantly regulated by the presence of coactivators and corepressors than by PXR protein expression. To date, there is scarce information on the regulation of PXR in HNSCC and on its role in the pathogenesis of this disease. Coactivator and corepressor expression was screened through qRT-PCR in 8 HNSCC cell lines and correlated to PXR activity, determined by using a reporter gene assay. All cell lines considerably expressed all the cofactors assessed. PXR activity negatively correlated with nuclear receptor corepressor 2 (NCoR2) expression, indicating a major role of this corepressor in PXR modulation and suggesting its potential as a surrogate for PXR activity in HNSCC. To test the association of NCoR2 with the malignant phenotype, a subset of three cell lines was transfected with an over-expression plasmid for this corepressor. Subsequently, cell growth and chemoresistance assays were performed. To elucidate the mechanisms underlying NCoR2 effects on cell growth, caspase 3/7 activity and protein levels of cleaved caspase 3 and PARP were evaluated. In HNO97 cells, NCoR2 over-expression decreased cell growth, chemoresistance and increased cleaved caspase 3 levels, caspase activity and cleaved PARP levels. On the contrary, in HNO124 and HNO210 cells, NCoR2 over-expression increased cell growth, drug resistance and decreased cleaved caspase 3 levels, caspase activity and cleaved PARP levels. In conclusion, we demonstrated a role of PXR and NCoR2 in the modulation of cell growth in HNSCC. This may contribute to a better understanding of the highly variable HNSCC therapeutic response.
Highlights
Head and neck squamous cell carcinoma (HNSCC) comprises malignancies of the oral cavity, larynx, pharynx, nasal cavity and paranasal sinuses, representing the sixth most frequent cancer worldwide
To evaluate the modulation of cell growth by pregnane X receptor (PXR), the expression of the nuclear receptor was silenced in HNO97, HNO124 and HNO210 cells using a specific short hairpin RNA (shRNA)
We described opposite effects of PXR on cell growth in HNSCC according to the particular cell line (Fig 1)
Summary
Head and neck squamous cell carcinoma (HNSCC) comprises malignancies of the oral cavity, larynx, pharynx, nasal cavity and paranasal sinuses, representing the sixth most frequent cancer worldwide. Wang et al described a PXR-driven increase in cell proliferation and metastatic potential in colon cancer [3]. In line with these observations, an induction of the anti-apoptotic genes bcl-2 and bcl-xL and a down-regulation of the pro-apoptotic genes BAK1 and p53 by PXR were reported [4,5]. Similar anti-apoptotic and pro-proliferative functions of PXR have been reported in models of breast-, endometrial-, ovarian- and prostate cancer [6]. An anti-proliferative and pro-apoptotic role of PXR was described in cervical cancer [7]. The expression of PXR in HNSCC is well-known [8], the impact of PXR on the malignant phenotype in HNSCC has not been investigated yet
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