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.