Regulatory Role of Hexokinase 2 in Modulating Head and Neck Tumorigenesis

Frontiers in Oncology

Wan-Chun Li¹  Chien-Ling Huang³  Chung-Ji Liu⁴  Jeng-Fan Lo⁶  Kuo-Wei Chang⁶  Chang-Yi Chen⁷  Yi-Ta Hsieh⁷  Li-Hao Cheng⁷  Chien-Hsiang Huang⁷  Tsai-Ying Chen⁷  Hsin-Ming Chen⁸ 

[1] Cancer Progression Research Center, National Yang-Ming University, Taipei, Taiwan;Department of Dentistry, School of Dentistry, National Yang-Ming University, Taipei, Taiwan;Department of Health Technology and Informatics (HTI), The Hong Kong Polytechnic University (PolyU), Kowloon, Hong Kong;Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan;Department of Oral and Maxillofacial Surgery, MacKay Memorial Hospital, Taipei, Taiwan;Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan;Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei, Taiwan;School of Dentistry and Department of Dentistry, National Taiwan University Medical College and National Taiwan University Hospital, Taipei, Taiwan;

关键词: head and neck cancer;    hexokinase 2;    cellular malignancy;    metabolic shift;    therapeutic efficacy;   

DOI  :  10.3389/fonc.2020.00176

来源: DOAJ

【 摘 要 】

To support great demand of cell growth, cancer cells preferentially obtain energy and biomacromolecules by glycolysis over mitochondrial oxidative phosphorylation (OxPhos). Among all glycolytic enzymes, hexokinase (HK), a rate-limiting enzyme at the first step of glycolysis to catalyze cellular glucose into glucose-6-phosphate, is herein emphasized. Four HK isoforms, HK1-HK4, were discovered in nature. It was shown that HK2 expression is enriched in many tumor cells and correlated with poorer survival rates in most neoplastic cells. HK2-mediated regulations for cell malignancy and mechanistic cues in regulating head and neck tumorigenesis, however, are not fully elucidated. Cellular malignancy index, such as cell growth, cellular motility, and treatment sensitivity, and molecular alterations were determined in HK2-deficient head and neck squamous cell carcinoma (HNSCC) cells. By using various cancer databases, HK2, but not HK1, positively correlates with HNSCC progression in a stage-dependent manner. A high HK2 expression was detected in head and neck cancerous tissues compared with their normal counterparts, both in mouse and human subjects. Loss of HK2 in HNSCC cells resulted in reduced cell (in vitro) and tumor (in vivo) growth, as well as decreased epithelial-mesenchymal transition–mediated cell movement; in contrast, HK2-deficient HNSCC cells exhibited greater sensitivity to chemotherapeutic drugs cisplatin and 5-fluorouracil but are more resistant to photodynamic therapy, indicating that HK2 expression could selectively define treatment sensitivity in HNSCC cells. At the molecular level, it was found that HK2 alteration drove metabolic reprogramming toward OxPhos and modulated oncogenic Akt and mutant TP53-mediated signals in HNSCC cells. In summary, the present study showed that HK2 suppression could lessen HNSCC oncogenicity and modulate therapeutic sensitivity, thereby being an ideal therapeutic target for HNSCCs.

【 授权许可】

Unknown