Regulatory Role of Hexokinase 2 in Modulating Head and Neck Tumorigenesis

Abstract

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.

Seven-Gene Signature Based on Glycolysis Is Closely Related to the Prognosis and Tumor Immune Infiltration of Patients With Gastric Cancer

“…To research reciprocal actions among these GRGs, we put the 326 GRGs into Cytoscape to create gene-gene interaction networks ( Figure 2B ). Cancer-associated proteins, such as GPI (glucose-6-phosphate isomerase), PKG1 (phosphoglycerate kinase 1) and HK (hexokinase), were identified to be major hubs in the resulting networks, which had previously been reported for their association with tumorigenesis ( 39 – 41 ).…”

Glycolysis-induced drug resistance in tumors—A response to danger signals?

“…First, drug resistance may be due to “qualitative” differences between glycolytic enzymes that are normally expressed and those that are expressed upon a metabolic switch in tumor cells. Thus, in some experimental systems, some (e.g., HK2, PKM2, PFKFB3), but not other isoforms of glycolytic enzymes were able to induce drug resistance [46 , 49 , 60 , 151] . In other instances, drug resistance was induced upon post-translational modifications of glycolytic enzymes [46 , 49] .…”

“…These modifications have been called danger-associated metabolic modifications [157] . We propose that a similar situation may exist in tumor cells, that is, intracellular or extracellular stimuli/danger signals induce danger-associated metabolic modifications in tumor cells such as an altered glycolytic metabolism displaying qualitative (e.g., expression of embryonic enzyme isoforms or posttranslational modifications) [35 , 46 , 49 , 60 , 151 , 152] or quantitative changes (overexpression of enzymes or overproduction of metabolites) [16 , 24 , 51 , 97 , 153] that activate molecular mechanisms (discussed under section "Mechanisms underlying glycolysis-induced drug resistance") which eventually lead to drug resistance. While such a model rests on an apparent symmetry between tumor cells and innate immune cells, known target molecules of glycolytic enzymes or metabolites that are involved in the induction drug resistance in tumor cells cannot be classified as PRR or non-PRR, as currently defined [156] .…”

A Novel Prognostic Index Based on the Analysis of Glycolysis-Related Genes in Head and Neck Squamous Cell Carcinomas

“…The expression of HMMR may be an effective prognostic marker in progression-free survival of patients with the papillary subtype of bladder cancer [ 36 ]. Hexokinase (HK), a rate-limiting enzyme catalyzing the first step of glycolysis, has four known subtypes: HK1–HK4 [ 37 ]. Although most studies focused on HK2, some studies found that the expression of HK1 is connected with disease progression, invasion, and poor survival in patients with esophageal squamous cell carcinoma [ 38 ].…”