1. Academic Validation
  2. Ketohexokinase-A deficiency attenuates the proliferation via reducing β-catenin in gastric cancer cells

Ketohexokinase-A deficiency attenuates the proliferation via reducing β-catenin in gastric cancer cells

  • Exp Cell Res. 2024 May 1;438(1):114038. doi: 10.1016/j.yexcr.2024.114038.
Gang Ma 1 Siya Liu 1 Fenglin Cai 1 Han Liang 1 Jingyu Deng 1 Rupeng Zhang 1 Mingzhi Cai 2
Affiliations

Affiliations

  • 1 Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, China; Tianjin Key Laboratory of Digestive Cancer, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
  • 2 Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, China; Tianjin Key Laboratory of Digestive Cancer, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China. Electronic address: tsaimingzhi@163.com.
Abstract

Overconsumption of fructose is closely related to Cancer. Ketohexokinase (KHK) catalyzes the conversion from fructose to fructose-1-phosphate (F1P), which is the first and committed step of fructose metabolism. Recently, aberrant KHK activation has been identified in multiple malignancies. However, the roles of KHK in gastric Cancer (GC) cells are largely unclear. Herein, we reveal that the expression of ketohexokinase-A (KHK-A), one alternatively spliced KHK isoform that possesses low affinity for fructose, was markedly increased in GC cells. Depletion of endogenous KHK-A expression using lentiviruses encoding short hairpin RNAs (shRNAs) or pharmaceutical disruption of KHK-A activity using KHK-IN-1 hydrochloride in GC NCI-N87 and HGC-27 cells inhibited the proliferation in vitro and in vivo. Additionally, the mitochondrial respiration in the GC cells with KHK-A deficiency compared with the control cells was significantly impaired. One commercially-available antibody array was used to explore the effects of KHK-A knockdown on signaling pathways, showing that β-catenin was remarkably reduced in the KHK-A deficient GC cells compared with the control ones. Pharmaceutical reduction in β-catenin levels slowed down the proliferation of GC cells. These data uncover that KHK-A promotes the proliferation in GC cells, indicating that this Enzyme might be a promising therapeutical target for GC treatment.

Keywords

Gastric cancer; KHK-IN-1 hydrochloride; Ketohexokinase-A; Proliferation; β-catenin.

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