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The decrease of glycolytic enzyme hexokinase 1 accelerates tumor malignancy via deregulating energy metabolism but

Po-Lin Tseng1,2, Chih-Wei Chen3,4,5, Keng-Hsun Hu6

  • 1Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 302, Taiwan.

Oncotarget
|May 4, 2018
PubMed

Insights

Silencing hexokinase 1 (HK1) in cancer cells alters energy metabolism, promoting tumor growth and metastasis. However, HK1-silenced cells become more vulnerable to 2-deoxyglucose (2-DG) treatment, suggesting targeted therapies.

Area of Science:

  • Cancer Biology
  • Metabolic Reprogramming
  • Tumorigenesis

Background:

  • Malignant tumors exhibit altered energy metabolism, primarily glycolysis (Warburg effect), for adenosine triphosphate (ATP) production.
  • Understanding these metabolic shifts is crucial for developing effective anti-cancer therapeutics.
  • Hexokinase (HK) enzymes are key regulators of glycolysis.

Purpose of the Study:

  • To investigate the role of attenuating glycolytic activity by silencing hexokinase (HK) isozymes HK1 and HK2 in tumor progression.
  • To explore the impact of HK1 and HK2 modulation on cancer cell metabolism, phenotype, and therapeutic susceptibility.

Main Methods:

  • Examined the effects of silencing hexokinase (HK) isozymes HK1 and HK2 in human cancer cells, specifically cervical carcinoma.
  • Utilized in vitro and in vivo analyses to assess tumor growth, metastasis, and phenotypic changes (epithelial-mesenchymal transition).
  • Analyzed cellular energy metabolism, including aerobic respiration, glycolysis, ATP generation, and key enzyme expression levels (HK1, HK2, lactate dehydrogenase 1, citrate synthase).

Main Results:

  • Silencing HK1, but not HK2, induced an epithelial-mesenchymal transition (EMT) phenotype, accelerating tumor growth and metastasis.
  • HK1 knockdown disrupted aerobic respiration, increased glycolysis, and enhanced glucose dependency without affecting ATP levels.
  • HK1-silenced cells showed increased susceptibility to 2-deoxyglucose (2-DG) induced proliferation inhibition.

Conclusions:

  • Silencing HK1 significantly alters cancer cell energy metabolism and promotes malignancy via EMT, while increasing sensitivity to 2-DG.
  • The study highlights an inverse correlation between HK1 and HK2 expression in cancer cells.
  • Results suggest that glycolytic inhibitors like 2-DG may be effective for cancers with elevated glycolytic activity, specifically those influenced by HK1.
Keywords:
Warburg effectglycolysishexokinase 1 (HK1)hexokinase 2 (HK2)tumor metastasis

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