Rare sugar L-sorbose exerts antitumor activity by impairing glucose metabolism
Hui-Lin Xu1, Xiaoman Zhou1, Shuai Chen1
1Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, 214122, China.
Abstract:
Rare sugars are monosaccharides with low natural abundance. They are structural isomers of dietary sugars, but hardly be metabolized. Here, we report that rare sugar L-sorbose induces apoptosis in various cancer cells. As a C-3 epimer of D-fructose, L-sorbose is internalized via the transporter GLUT5 and phosphorylated by ketohexokinase (KHK) to produce L-sorbose-1-phosphate (S-1-P). Cellular S-1-P inactivates the glycolytic enzyme hexokinase resulting in attenuated glycolysis. Consequently, mitochondrial function is impaired and reactive oxygen species are produced. Moreover, L-sorbose downregulates the transcription of KHK-A, a splicing variant of KHK. Since KHK-A is a positive inducer of antioxidation genes, the antioxidant defense mechanism in cancer cells can be attenuated by L-sorbose-treatment. Thus, L-sorbose performs multiple anticancer activities to induce cell apoptosis. In mouse xenograft models, L-sorbose enhances the effect of tumor chemotherapy in combination with other anticancer drugs. These results demonstrate L-sorbose as an attractive therapeutic reagent for cancer treatment.
Insights
Rare sugar L-sorbose induces cancer cell apoptosis by disrupting glycolysis and antioxidant defenses. It also enhances chemotherapy efficacy in preclinical models, showing potential as a novel cancer therapeutic.
Area of Science:
- Biochemistry
- Oncology
- Metabolic pathways
Background:
- Rare sugars are isomers of common sugars with limited metabolic activity.
- Cancer cells exhibit altered metabolic pathways, presenting therapeutic targets.
Purpose of the Study:
- To investigate the anticancer effects of the rare sugar L-sorbose.
- To elucidate the molecular mechanisms underlying L-sorbose-induced cancer cell death.
Main Methods:
- Cellular uptake and phosphorylation of L-sorbose via GLUT5 and ketohexokinase (KHK).
- Assessment of glycolysis, mitochondrial function, and reactive oxygen species (ROS) production.
- Analysis of KHK-A gene expression and its role in antioxidant defense.
- Evaluation of L-sorbose in combination chemotherapy using mouse xenograft models.
Main Results:
- L-sorbose triggers apoptosis in diverse cancer cell lines.
- It inhibits glycolysis by inactivating hexokinase, leading to impaired mitochondrial function and increased ROS.
- L-sorbose downregulates KHK-A, reducing the expression of antioxidant genes.
- Combination therapy with L-sorbose improved chemotherapeutic outcomes in vivo.
Conclusions:
- L-sorbose exhibits multifaceted anticancer activities by inducing apoptosis through metabolic disruption and attenuation of antioxidant defenses.
- L-sorbose demonstrates potential as an adjuvant therapeutic agent to enhance conventional cancer chemotherapy.
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