Docetaxel suppressed cell proliferation through Smad3/HIF-1α-mediated glycolysis in prostate cancer cells

BACKGROUND: Tumor glycolysis is a critical event for tumor progression. Docetaxel is widely used as a first-line drug for chemotherapy and shown to have a survival advantage. However, the role of docetaxel in tumor glycolysis remained poorly understood. METHODS: The effect of Docetaxel in tumor glycolysis and proliferation were performed by CCK-8, Western blotting, real-time PCR, glucose, and lactate detection and IHC. ChIP and luciferase assay were used to analyze the mechanism of Docetaxel on Smad3-mediated HIF-1α transactivity. RESULTS: In this study, we showed that docetaxel treatment led to a significant inhibition of cell proliferation in prostate cancer cells through PFKP-mediated glycolysis. Addition of lactate, a production of glycolysis, could reverse the inhibitory effect of docetaxel on cell proliferation. Further analysis has demonstrated that phosphorylation of Smad3 (Ser213) was drastically decreased in response to docetaxel stimulation, leading to reduce Smad3 nuclear translocation. Luciferase and Chromatin immunoprecipitation (ChIP) analysis revealed that docetaxel treatment inhibited the binding of Smad3 to the promoter of the HIF-1α gene, suppressing transcriptional activation of HIF-1α. Moreover, ectopic expression of Smad3 in prostate cancer cells could overcome the decreased HIF-1α expression and its target gene PFKP caused by docetaxel treatment. Most importantly, endogenous Smad3 regulated and interacted with HIF-1α, and this interaction was destroyed in response to docetaxel treatment. What’s more, both HIF-1α and PFKP expression were significantly reduced in prostate cancer received docetaxel treatment in vivo. CONCLUSION: These findings extended the essential role of docetaxel and revealed that docetaxel inhibited cell proliferation by targeting Smad3/HIF-1α signaling-mediated tumor Warburg in prostate cancer cells. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12964-022-00950-z.