The decrease of glycolytic enzyme hexokinase 1 accelerates tumor malignancy via deregulating energy metabolism but sensitizes cancer cells to 2-deoxyglucose inhibition

Po Lin Tseng, Chih Wei Chen, Keng Hsun Hu, Hung Chi Cheng, Yuan Ho Lin, Wen Hui Tsai, Tain Junn Cheng, Wei Hsuan Wu, Chin Wei Yeh, Chin Chih Lin, Hui Ju Tsai, Hao Chun Chang, Jiin Haur Chuang, Yan Shen Shan, Wen Tsan Chang

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Malignant tumors often display an aberrant energy metabolism that relies primarily on glycolysis to produce adenosine triphosphate (ATP) the so-called Warburg effect or aerobic glycolysis. Thus, the elucidation of this energetic alteration in malignant tumors is important in the search for more effective therapeutics against malignant cancers, the most deadly human disease. To investigate whether attenuated glycolytic activity modulates tumor progression, the effects of silencing the first and rate-limiting glycolytic enzyme hexokinase (HK) isozymes HK1 and HK2 were examined. There was an inverse correlation between the expression of HK1 and HK2 in human cancer cells. In cervical carcinoma cells, the HK1 but not HK2 knockdown induced a phenotypic change characteristic of epithelial-mesenchymal transition, which accelerated tumor growth and metastasis both in vitro and in vivo analyses. Notably, the silencing of HK1 disrupted aerobic respiration and increased glycolysis, but it had no effect on ATP generation. These metabolic changes were associated with higher HK2 and lactate dehydrogenase 1 expression but a lower citrate synthase level. Particularly, the HK1 knockdown induced aberrant energy metabolism that was almost recapitulated by HK2 overexpression. Moreover, the HK1-silenced cells showed strong glucose-dependent growth and 2-deoxyglucose (2-DG) induced cell proliferation inhibition. These results clearly indicate that the silencing of HK1, but not HK2, alters energy metabolism and induces an EMT phenotype, which enhances tumor malignancy, but increases the susceptibility of cancer cells to 2-DG inhibition. In addition, this work also suggests that the glycolytic inhibitors should be used only to treat cancers with elevated glycolytic activity.

Original languageEnglish
Pages (from-to)18949-18969
Number of pages21
JournalOncotarget
Volume9
Issue number27
DOIs
Publication statusPublished - 2018 Apr 10

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Hexokinase
Deoxyglucose
Energy Metabolism
Enzymes
Neoplasms
Glycolysis
Adenosine Triphosphate
Citrate (si)-Synthase
Epithelial-Mesenchymal Transition
Growth
Isoenzymes
Respiration
Cell Proliferation
Neoplasm Metastasis
Carcinoma
Phenotype
Glucose

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Tseng, Po Lin ; Chen, Chih Wei ; Hu, Keng Hsun ; Cheng, Hung Chi ; Lin, Yuan Ho ; Tsai, Wen Hui ; Cheng, Tain Junn ; Wu, Wei Hsuan ; Yeh, Chin Wei ; Lin, Chin Chih ; Tsai, Hui Ju ; Chang, Hao Chun ; Chuang, Jiin Haur ; Shan, Yan Shen ; Chang, Wen Tsan. / The decrease of glycolytic enzyme hexokinase 1 accelerates tumor malignancy via deregulating energy metabolism but sensitizes cancer cells to 2-deoxyglucose inhibition. In: Oncotarget. 2018 ; Vol. 9, No. 27. pp. 18949-18969.
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title = "The decrease of glycolytic enzyme hexokinase 1 accelerates tumor malignancy via deregulating energy metabolism but sensitizes cancer cells to 2-deoxyglucose inhibition",
abstract = "Malignant tumors often display an aberrant energy metabolism that relies primarily on glycolysis to produce adenosine triphosphate (ATP) the so-called Warburg effect or aerobic glycolysis. Thus, the elucidation of this energetic alteration in malignant tumors is important in the search for more effective therapeutics against malignant cancers, the most deadly human disease. To investigate whether attenuated glycolytic activity modulates tumor progression, the effects of silencing the first and rate-limiting glycolytic enzyme hexokinase (HK) isozymes HK1 and HK2 were examined. There was an inverse correlation between the expression of HK1 and HK2 in human cancer cells. In cervical carcinoma cells, the HK1 but not HK2 knockdown induced a phenotypic change characteristic of epithelial-mesenchymal transition, which accelerated tumor growth and metastasis both in vitro and in vivo analyses. Notably, the silencing of HK1 disrupted aerobic respiration and increased glycolysis, but it had no effect on ATP generation. These metabolic changes were associated with higher HK2 and lactate dehydrogenase 1 expression but a lower citrate synthase level. Particularly, the HK1 knockdown induced aberrant energy metabolism that was almost recapitulated by HK2 overexpression. Moreover, the HK1-silenced cells showed strong glucose-dependent growth and 2-deoxyglucose (2-DG) induced cell proliferation inhibition. These results clearly indicate that the silencing of HK1, but not HK2, alters energy metabolism and induces an EMT phenotype, which enhances tumor malignancy, but increases the susceptibility of cancer cells to 2-DG inhibition. In addition, this work also suggests that the glycolytic inhibitors should be used only to treat cancers with elevated glycolytic activity.",
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The decrease of glycolytic enzyme hexokinase 1 accelerates tumor malignancy via deregulating energy metabolism but sensitizes cancer cells to 2-deoxyglucose inhibition. / Tseng, Po Lin; Chen, Chih Wei; Hu, Keng Hsun; Cheng, Hung Chi; Lin, Yuan Ho; Tsai, Wen Hui; Cheng, Tain Junn; Wu, Wei Hsuan; Yeh, Chin Wei; Lin, Chin Chih; Tsai, Hui Ju; Chang, Hao Chun; Chuang, Jiin Haur; Shan, Yan Shen; Chang, Wen Tsan.

In: Oncotarget, Vol. 9, No. 27, 10.04.2018, p. 18949-18969.

Research output: Contribution to journalArticle

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AU - Tseng, Po Lin

AU - Chen, Chih Wei

AU - Hu, Keng Hsun

AU - Cheng, Hung Chi

AU - Lin, Yuan Ho

AU - Tsai, Wen Hui

AU - Cheng, Tain Junn

AU - Wu, Wei Hsuan

AU - Yeh, Chin Wei

AU - Lin, Chin Chih

AU - Tsai, Hui Ju

AU - Chang, Hao Chun

AU - Chuang, Jiin Haur

AU - Shan, Yan Shen

AU - Chang, Wen Tsan

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AB - Malignant tumors often display an aberrant energy metabolism that relies primarily on glycolysis to produce adenosine triphosphate (ATP) the so-called Warburg effect or aerobic glycolysis. Thus, the elucidation of this energetic alteration in malignant tumors is important in the search for more effective therapeutics against malignant cancers, the most deadly human disease. To investigate whether attenuated glycolytic activity modulates tumor progression, the effects of silencing the first and rate-limiting glycolytic enzyme hexokinase (HK) isozymes HK1 and HK2 were examined. There was an inverse correlation between the expression of HK1 and HK2 in human cancer cells. In cervical carcinoma cells, the HK1 but not HK2 knockdown induced a phenotypic change characteristic of epithelial-mesenchymal transition, which accelerated tumor growth and metastasis both in vitro and in vivo analyses. Notably, the silencing of HK1 disrupted aerobic respiration and increased glycolysis, but it had no effect on ATP generation. These metabolic changes were associated with higher HK2 and lactate dehydrogenase 1 expression but a lower citrate synthase level. Particularly, the HK1 knockdown induced aberrant energy metabolism that was almost recapitulated by HK2 overexpression. Moreover, the HK1-silenced cells showed strong glucose-dependent growth and 2-deoxyglucose (2-DG) induced cell proliferation inhibition. These results clearly indicate that the silencing of HK1, but not HK2, alters energy metabolism and induces an EMT phenotype, which enhances tumor malignancy, but increases the susceptibility of cancer cells to 2-DG inhibition. In addition, this work also suggests that the glycolytic inhibitors should be used only to treat cancers with elevated glycolytic activity.

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