HPV-associated differential regulation of tumor metabolism in oropharyngeal head and neck cancer

Abstract

HPV-positive oropharyngeal cancer patients experience significantly lower locoregional recurrence and higher overall survival in comparison with HPV-negative patients, especially among those who received radiation therapy. The goal of the present study is to investigate the molecular mechanisms underlying the differential radiation sensitivity between HPV-negative and HPV-positive head and neck squamous cell carcinoma (HNSCC). Here, we show that HPV-negative HNSCC cells exhibit increased glucose metabolism as evidenced by increased production of lactate, while HPV-positive HNSCC cells effectively utilize mitochondrial respiration as evidenced by increased oxygen consumption. HPV-negative cells express HIF1α and its downstream mediators of glucose metabolism such as hexokinase II (HKII) and carbonic anhydrase IX (CAIX) at higher levels, while the expression level of cytochrome c oxidase (COX) was noticeably higher in HPV-positive HNSCC. In addition, the expression levels of pyruvate dehydrogenase kinases (PDKs), which inhibit pyruvate dehydrogenase activity, thereby preventing entry of pyruvate into the mitochondrial tricarboxylic acid (TCA) cycle, were much higher in HPV-negative HNSCC compared to those in HPV-positive cells. Importantly, a PDK inhibitor, dichloroacetate, effectively sensitized HPV-negative cells to irradiation. Lastly, we found positive interactions between tonsil location and HPV positivity for COX intensity and COX/HKII index ratio as determined by immunohistochemical analysis. Overall survival of patients with HNSCC at the tonsil was significantly improved with an increased COX expression. Taken together, the present study provides molecular insights into the mechanistic basis for the differential responses to radiotherapy between HPV-driven vs. spontaneous or chemically induced oropharyngeal cancer.

β2-Adrenergic receptor modulates mitochondrial metabolism and disease progression in recurrent/metastatic HPV(+) HNSCC

“…In HNSCC, an immunohistochemical analysis of patient samples found evidence of heightened mitochondrial respiration in proliferative tumor cells, which the authors found to be especially common in high-grade lesions 36 . A similar upregulation of mitochondrial respiration in HNSCC has been attributed to HPV positivity 37 . These findings implicate mitochondrial metabolism in the pathogenesis and progression of at least certain subsets of cancers, including HNSCC; if in part regulated by β2AR, as suggested by the data herein, this may represent a therapeutically targetable pathway.…”

Hypoxia-Induced Centrosome Amplification Underlies Aggressive Disease Course in HPV-Negative Oropharyngeal Squamous Cell Carcinomas

“…Also, high HIF-1α expression strongly correlated with high CA in HPV-neg OPSCCs. Previously, however, separate studies have reported conflicting results regarding HIF-1α expression in HPV-pos versus HPV-neg tumors [38,39]. Other endogenous hypoxia markers such as CA IX have also not yielded definitive results [40].…”

“…For the genotyping of the viral DNA, the Luminex platform was used for bead-based array. The EIA detected 14 HPV types: 16,18,31,33,35,39,45,51,52,56,58,59,66,68. β-globin PCR was used to test for sample quality post-DNA extraction [43].…”

Hypoxia-inducible factor-1α activation in HPV-positive head and neck squamous cell carcinoma cell lines

“…However, the relative hypoxic expression signal and absolute protein increase was higher in the HPV-positive cell lines. Recently, it has been shown that HIF-1α protein accumulates in HPV-positive and -negative HNSCC cell lines under hypoxia [ 24 ], but no elevated accumulation of HIF-1α protein levels in the HPV-positive cell lines was detected under normoxic conditions [ 25 ]. In accordance with our investigations, earlier studies have shown HIF-1α stabilization by HPV under hypoxic conditions (chemically induced) in HPV E6/E7 oncoprotein transfected cells or cervical cell lines [ 6 , 8 , 26 ].…”