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 journalArticlepeer-review

4 Citations (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

All Science Journal Classification (ASJC) codes

  • Oncology

Fingerprint Dive into the research topics of 'The decrease of glycolytic enzyme hexokinase 1 accelerates tumor malignancy via deregulating energy metabolism but sensitizes cancer cells to 2-deoxyglucose inhibition'. Together they form a unique fingerprint.

Cite this