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D-mannose suppresses HIF-1α mediated metabolic reprogramming in clear cell renal cell carcinoma
Ziyin Tian1, Ruonan Zhang1, Yan Ma2
1Nourse Centre for Pet Nutrition, Wuhu, China.
Abstract:
The inactivation mutation of VHL drives the progression of clear cell renal cell carcinoma (ccRCC), while the deletion of VHL leads to the failure of HIF-1/2α to degrade normally through the ubiquitin proteasome pathway. Notably, the abnormal accumulation of HIF-1/2α results in metabolic reprogramming and promotes the occurrence of tumors. Therefore, inhibition of metabolic reprogramming of ccRCC may be an effective treatment. In methodology, the viabilities of tumor cells were detected by cell counting kit-8 assay in vitro. The expression levels of related proteins were analyzed by western blotting assay, and the mRNA levels of genes were assessed by RT-qPCR assay. Glucose uptake, intracellular lactate and NADPH production were measured according to relevant instructions. Here, we found that D-mannose inhibits the proliferation of ccRCC in vitro. Mechanistically, D-mannose suppresses the transcription of HIF-1α downstream target genes, including GLUT1, LDHA, PDK1 and VEGF, by downregulating the protein level of HIF-1α in ccRCC cells. Furthermore, D-mannose reduces glucose uptake and intracellular lactate and NADPH production. To sum up, this study demonstrates that targeting HIF-1α by D-mannose to inhibit metabolic reprogramming is a promising strategy for ccRCC and complements a previously unknown role of D-mannose in cancer treatment.
Insights
D-mannose inhibits clear cell renal cell carcinoma (ccRCC) progression by targeting HIF-1α. This sugar suppresses tumor cell proliferation and metabolic reprogramming, offering a novel therapeutic strategy for ccRCC.
Area of Science:
- Oncology
- Molecular Biology
- Metabolic Research
Background:
- Clear cell renal cell carcinoma (ccRCC) progression is driven by VHL inactivation mutations.
- VHL gene deletion impairs HIF-1/2α degradation, leading to abnormal accumulation.
- HIF-1/2α accumulation drives metabolic reprogramming and tumor development in ccRCC.
Purpose of the Study:
- To investigate the potential of inhibiting ccRCC metabolic reprogramming as a treatment strategy.
- To explore the effect of D-mannose on ccRCC proliferation and underlying mechanisms.
- To elucidate the role of D-mannose in targeting HIF-1α pathway in ccRCC.
Main Methods:
- Cell counting kit-8 assay for in vitro tumor cell viability.
- Western blotting for protein expression analysis.
- RT-qPCR for gene mRNA level assessment.
- Measurement of glucose uptake, lactate, and NADPH production.
Main Results:
- D-mannose significantly inhibits ccRCC cell proliferation in vitro.
- D-mannose downregulates HIF-1α protein levels in ccRCC cells.
- D-mannose suppresses the transcription of HIF-1α downstream targets (GLUT1, LDHA, PDK1, VEGF).
- D-mannose reduces glucose uptake, intracellular lactate, and NADPH production in ccRCC cells.
Conclusions:
- D-mannose effectively inhibits ccRCC proliferation by targeting HIF-1α.
- D-mannose disrupts metabolic reprogramming in ccRCC, presenting a promising therapeutic avenue.
- This study reveals a novel role for D-mannose in cancer treatment by modulating the HIF-1α pathway.
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