Poor prognosis of hexokinase 2 overexpression in solid tumors of digestive system: a meta-analysis

Zhou, Haihong; Hu, Liren; Wu, Fenping; Zou, Lei; He, Taiping

doi:10.18632/oncotarget.15974

Cited by 65 publications

(60 citation statements)

References 52 publications

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“…Moreover, given its selective expression in tumors, HK2 has drawn increasing attention on its clinical implications forming the basis of fluorodeoxyglucose F-18 positron emission tomography imaging, a widely used clinical procedure to detect tumors. Indeed, 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).…”

Section: Introductionmentioning

confidence: 99%

Regulatory Role of Hexokinase 2 in Modulating Head and Neck Tumorigenesis

Huang²,

Hsieh³

et al. 2020

Front. Oncol.

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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.

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Section: Introductionmentioning

confidence: 99%

Regulatory Role of Hexokinase 2 in Modulating Head and Neck Tumorigenesis

Huang²,

Hsieh³

et al. 2020

Front. Oncol.

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“…However, it is the dysfunction of cancer cell metabolism that conferred the Warburg Effect 152 , while targeting this phenotype could be a strategy to expose tumour in an unfavourable micro-environment. This hypothesis has inspired many scientists to focus on several enzymes that would be crucial in the process of cell metabolism, such as glucose transporters (GLUTs) 153 , hexokinase2 (HK2) 154 , pyruvate kinase M2 (PKM2) 155 , pyruvate dehydrogenase kinase (PDK) 156 , and lactate dehydrogenase-A (LDHA) 157 . A number of inhibitors that target those specific enzymes have been developed as potential anti-cancer agents 158 .…”

Section: Discussionmentioning

confidence: 99%

Combination Strategies Using EGFR-TKi in NSCLC Therapy: Learning from the Gap between Pre-Clinical Results and Clinical Outcomes

Zheng

Tam

2018

Int. J. Biol. Sci.

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Although epidermal growth factor receptor (EGFR) inhibitors have been used to treat non-small cell lung cancer (NSCLC) for decades with great success in patients with EGFR mutations, acquired resistance inevitably occurs after long-term exposure. More recently, combination therapy has emerged as a promising strategy to overcome this issue. Several experiments have been carried out to evaluate the synergism of combination therapy both in vitro and in vivo. Additionally, many clinical studies have been carried out to investigate the feasibility of treatment with EGFR-tyrosine kinase inhibitors (TKi) combined with other NSCLC treatments, including radiotherapy, cytotoxic chemotherapies, targeted therapies, and emerging immunotherapies. However, a significant gap still exists when applying pre-clinical results to clinical scenarios, which hinders the development and use of these strategies. This article is a literature review analysing the rationalities and controversies in the transition from pre-clinical investigation to clinical practice associated with various combination strategies. It also highlights clues and challenges regarding future combination therapeutic options in NSCLC treatment.

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“…*P < 0.05 produce glucose-6-phosphate [31]. Previous studies have confirmed that the expression of HK2 is significantly upregulated in many cancers and its high expression in cancers is associated with poor prognosis [30,[32][33][34][35]. Administration of HK2 inhibitor, 2-DG, can induce cancer cell death by abrogating intracellular glycolysis.…”

Section: Discussionmentioning

confidence: 97%

FOXE1 represses cell proliferation and Warburg effect by inhibiting HK2 in colorectal cancer

Dai

Meng

et al. 2020

Cell Commun Signal

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Background: Low expression of FOXE1, a member of Forkhead box (FOX) transcription factor family that plays vital roles in cancers, contributes to poor prognosis of colorectal cancer (CRC) patients. However, the underlying mechanism remains unclear. Materials and methods: The effects of FOXE1 on the growth of colon cancer cells and the expression of glycolytic enzymes were investigated in vitro and in vivo. Molecular biological experiments were used to reveal the underlying mechanisms of altered aerobic glycolysis. CRC tissue specimens were used to determine the clinical association of ectopic metabolism caused by dysregulated FOXE1. Results: FOXE1 is highly expressed in normal colon tissues compared with cancer tissues and low expression of FOXE1 is significantly associated with poor prognosis of CRC patients. Silencing FOXE1 in CRC cell lines dramatically enhanced cell proliferation and colony formation and promoted glucose consumption and lactate production, while enforced expression of FOXE1 manifested the opposite effects. Mechanistically, FOXE1 bound directly to the promoter region of HK2 and negatively regulated its transcription. Furthermore, the expression of FOXE1 in CRC tissues was negatively correlated with that of HK2. Conclusion: FOXE1 functions as a critical tumor suppressor in regulating tumor growth and glycolysis via suppressing HK2 in CRC.

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Poor prognosis of hexokinase 2 overexpression in solid tumors of digestive system: a meta-analysis

Cited by 65 publications

References 52 publications

Regulatory Role of Hexokinase 2 in Modulating Head and Neck Tumorigenesis

Regulatory Role of Hexokinase 2 in Modulating Head and Neck Tumorigenesis

Combination Strategies Using EGFR-TKi in NSCLC Therapy: Learning from the Gap between Pre-Clinical Results and Clinical Outcomes

FOXE1 represses cell proliferation and Warburg effect by inhibiting HK2 in colorectal cancer

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