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. 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. 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. 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.

中文翻译：

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多西紫杉醇通过 Smad3/HIF-1α 介导的前列腺癌细胞糖酵解抑制细胞增殖

肿瘤糖酵解是肿瘤进展的关键事件。多西紫杉醇被广泛用作化疗的一线药物，并显示出具有生存优势。然而，多西紫杉醇在肿瘤糖酵解中的作用仍知之甚少。多西紫杉醇对肿瘤糖酵解和增殖的影响通过CCK-8、Western blotting、real-time PCR、葡萄糖和乳酸盐检测以及IHC来进行。ChIP 和荧光素酶测定用于分析多西紫杉醇对 Smad3 介导的 HIF-1α 转活性的机制。在这项研究中，我们发现多西紫杉醇治疗通过 PFKP 介导的糖酵解显着抑制前列腺癌细胞的细胞增殖。添加乳酸（糖酵解的产物）可以逆转多西紫杉醇对细胞增殖的抑制作用。进一步的分析表明，Smad3 (Ser213) 的磷酸化在对多西紫杉醇刺激的反应中显着降低，从而导致 Smad3 核转位减少。荧光素酶和染色质免疫沉淀 (ChIP) 分析表明，多西紫杉醇处理可抑制 Smad3 与 HIF-1α 基因启动子的结合，从而抑制 HIF-1α 的转录激活。此外，Smad3 在前列腺癌细胞中的异位表达可以克服多西紫杉醇治疗引起的 HIF-1α 表达及其靶基因 PFKP 的降低。最重要的是，内源性 Smad3 调节 HIF-1α 并与其相互作用，而这种相互作用在多西紫杉醇治疗后被破坏。此外，在体内接受多西紫杉醇治疗的前列腺癌中，HIF-1α 和 PFKP 的表达均显着降低。