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.
Highlights
Most cancers have acquired the same set of functional capabilities during tumorigenesis including sustained proliferative signal, evaded growth suppressors, resisted cell death, sustained angiogenesis, and deregulated cellular energetics [1]
Immunohistochemical analysis showed that HK2 is strongly detected in 4-nitroquinoline 1-oxide (4-NQO)–induced mouse tongue neoplastic lesions compared with normal oral epithelium (Figure 1G), as well as human oral squamous cell carcinoma (Figure 1H)
It was shown that HK2 loss downregulated cell growth, epithelial–mesenchymal transition (EMT)-mediated cell movement, FIGURE 4 | HK2 loss modulated therapeutic sensitivity in head and neck squamous cell carcinoma (HNSCC) Cells. (A) Decreased IC50 for clinical chemotherapeutic agent CDDP and 5-FU, whereas (B) greater resistance in response to photodynamic therapy was detected in HK2-deficient HNSCC cells
Summary
Most cancers have acquired the same set of functional capabilities during tumorigenesis including sustained proliferative signal, evaded growth suppressors, resisted cell death, sustained angiogenesis, and deregulated cellular energetics [1]. HK2 is rarely expressed in normal tissues as a high level of HK2 expression was detected in many solid tumors [14] and is associated with elevated progression, poorer overall survival, and treatment resistance in breast cancer (both primary and metastatic kinds) [15,16,17,18], bladder cancer [19], cervical squamous cell carcinoma [20], colorectal cancer [21], epithelial ovarian tumors [22], glioblastoma multiforme [23], hepatocellular carcinoma [24], laryngeal squamous cell carcinoma [25], lung cancer [26], neuroblastoma [27], neuroendocrine tumor [28], pancreatic cancer [29], and prostate cancer [30], making it an excellent target for development of anticancer therapy. A recent meta-analysis provides evidence that HK2 could be a marker to predict the risk of all-cause mortality and cancer progression in patients with tumors of the digestive system [31]
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