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

// Young-Suk Jung 1, 7, * , Abdo J. Najy 1, * , Wei Huang 1 , Seema Sethi 1 , Michael Snyder 2, 3 , Wael Sakr 1 , Gregory Dyson 2 , Maik Huttemann 4 , Icksoo Lee 4, 8 , Rouba Ali-Fehmi 1 , Silvia Franceschi 5 , Linda Struijk 6 , Harold E. Kim 2, 3 , Ikuko Kato 2, 1 and Hyeong-Reh Choi Kim 1 1 Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA 2 Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA 3 Division of Radiation Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA 4 Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA 5 International Agency for Research on Cancer, Lyon, France 6 DDL Diagnostic Laboratory, Rijswijk, The Netherlands 7 Current Address: Pusan National University College of Pharmacy, Geumjeong-gu, Busan, Republic of Korea 8 Current Address: College of Medicine, Dankook University, Cheonan-si, Chungcheongnam-do, Republic of Korea * These authors have contributed equally to this work Correspondence to: Hyeong-Reh Choi Kim, email: hrckim@med.wayne.edu Keywords: head and neck squamous cell carcinoma, human papillomavirus, radiation, glucose metabolism, mitochondrial respiration Received: November 04, 2016     Accepted: April 05, 2017     Published: May 16, 2017 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.