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A novel small molecule glycolysis inhibitor WZ35 exerts anti-cancer effect via metabolic reprogramming
Lihua Wang1,2, Zheng Zhu3, Qi Liang4
1School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
Background:
Liver cancer is the fifth leading cause of cancer death worldwide, but early diagnosis and treatment of liver cancer remains a clinical challenge. How to screen and diagnose liver cancer early and prolong the survival rate is still the focus of researchers.
Methods:
Cell experiments were used to detect the effect of WZ35 on the colony formation ability and proliferation activity of hepatoma cells, nude mouse experiment to observe the in vivo anticancer activity and toxic side effects of WZ35; metabolomics analysis, glucose metabolism experiment and Seahorse analysis of liver cancer cells treated with WZ35; cell experiments combined with bioinformatics analysis to explore the mechanism of WZ35-mediated metabolic reprogramming to exert anticancer activity; tissue microarray and case analysis to evaluate the clinical significance of biomarkers for early diagnosis, treatment and prognosis evaluation of liver cancer.
Results:
WZ35 inhibited the proliferation activity of various cell lines of liver cancer, and showed good therapeutic effect in nude mice model of hepatocellular carcinoma without obvious toxic and side effects; WZ35 inhibited the absorption of glucose in hepatoma cells, and the drug effect glycolysis, phosphorylation and purine metabolism are relatively seriously damaged; WZ35 mainly inhibits YAP from entering the nucleus as a transcription factor activator by activating oxidative stress in liver cancer cells, reducing the transcription of GLUT1, and finally reducing its GLUT1. Tissue microarray and case analysis showed that GLUT1 and YAP were highly expressed and correlated in liver cancer patients, and were associated with poor patient prognosis. The GLUT1-YAP risk model had a high score in predicting prognosis.
Conclusion:
The study confirms that WZ35 is a small molecule glycolysis inhibitor, and through its properties, it mediates metabolic reprogramming dominated by impaired glycolysis, oxidative phosphorylation and purine metabolism to inhibit the proliferation activity of liver cancer cells. Our findings present novel insights into the pathology of liver cancer and potential targets for new therapeutic strategies. GLUT1-YAP has important reference significance for predicting the stages of disease progression in liver cancer patients and have the potential to serve as novel biomarkers for the diagnosis and treatment of liver cancer.
Insights
WZ35, a small molecule glycolysis inhibitor, effectively reduces liver cancer cell proliferation by disrupting glucose metabolism and inhibiting YAP. The GLUT1-YAP model shows promise for diagnosing and predicting liver cancer prognosis.
Area of Science:
- Oncology
- Molecular Biology
- Metabolic Research
Background:
- Liver cancer is a leading cause of cancer mortality globally.
- Early diagnosis and effective treatment of liver cancer remain significant clinical challenges.
- Identifying novel therapeutic targets and biomarkers for liver cancer is crucial for improving patient survival rates.
Purpose of the Study:
- To investigate the anti-cancer effects of WZ35 on liver cancer cells.
- To elucidate the mechanism of WZ35-induced metabolic reprogramming in liver cancer.
- To evaluate the potential of GLUT1 and YAP as biomarkers for liver cancer diagnosis and prognosis.
Main Methods:
- In vitro cell experiments assessing WZ35's impact on hepatoma cell proliferation and colony formation.
- In vivo studies using a nude mouse model to evaluate WZ35's anti-cancer activity and toxicity.
- Metabolomics, glucose metabolism assays, and Seahorse analysis to understand WZ35's effects on cellular metabolism.
- Bioinformatics and tissue microarray analysis to explore WZ35's mechanism and validate biomarkers.
Main Results:
- WZ35 demonstrated significant inhibition of liver cancer cell proliferation in vitro and in vivo without notable toxicity.
- WZ35 treatment impaired glycolysis, oxidative phosphorylation, and purine metabolism in hepatoma cells.
- WZ35 inhibits YAP nuclear entry by activating oxidative stress, reducing GLUT1 transcription, and consequently decreasing glucose uptake.
- High expression of GLUT1 and YAP in liver cancer patients correlated with poor prognosis, and a GLUT1-YAP risk model effectively predicted outcomes.
Conclusions:
- WZ35 acts as a small molecule glycolysis inhibitor, inducing metabolic reprogramming to suppress liver cancer cell proliferation.
- The findings offer new insights into liver cancer pathology and identify potential therapeutic targets.
- The GLUT1-YAP axis presents significant potential as a biomarker for predicting disease progression and as a target for liver cancer diagnosis and treatment.
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