Data Sheet 3_Anticarcinogenic effects of ursodeoxycholic acid in pancreatic adenocarcinoma cell models.zip

Changes to the composition of the microbiome in neoplasia, is termed oncobiosis, may affect tumor behavior through the changes to the secretion of bacterial metabolites. In this study we show, that ursodeoxycholic acid (UDCA), a bacterial metabolite, has cytostatic properties in pancreatic adenocarcinoma cell (PDAC) models. UDCA in concentrations corresponding to the human serum reference range suppressed PDAC cell proliferation. UDCA inhibited the expression of epithelial mesenchymal transition (EMT)-related markers and invasion capacity of PDAC cells. UDCA treatment increased oxidative/nitrosative stress by reducing the expression of nuclear factor, erythroid 2-like 2 (NRF2), inducing inducible nitric oxide synthase (iNOS) and nitrotyrosine levels and enhancing lipid peroxidation. Furthermore, UDCA reduced the expression of cancer stem cell markers and the proportion of cancer stem cells. Suppression of oxidative stress by antioxidants, blunted the UDCA-induced reduction in cancer stemness. Finally, we showed that UDCA induced mitochondrial oxidative metabolism. UDCA did not modulate the effectiveness of chemotherapy agents used in the chemotherapy treatment of pancreatic adenocarcinoma. The antineoplastic effects of UDCA, observed here, may contribute to the induction of cytostasis in PDAC cell models by providing a more oxidative/nitrosative environment.

肿瘤发生过程中微生物组组成的改变被称为肿瘤微生态失调（oncobiosis），其可通过调控细菌代谢产物的分泌来影响肿瘤的生物学行为。本研究证实，细菌代谢产物熊去氧胆酸（ursodeoxycholic acid, UDCA）在胰腺腺癌（pancreatic adenocarcinoma, PDAC）细胞模型中具有细胞生长抑制活性。浓度处于人体血清参考范围的UDCA可抑制胰腺腺癌细胞的增殖。UDCA可抑制上皮间质转化（epithelial mesenchymal transition, EMT）相关标志物的表达，并降低胰腺腺癌细胞的侵袭能力。UDCA处理可通过下调核因子红细胞2相关因子2（nuclear factor, erythroid 2-like 2, NRF2）的表达、诱导诱导型一氧化氮合酶（inducible nitric oxide synthase, iNOS）表达及硝基酪氨酸水平升高，并增强脂质过氧化反应，从而提升氧化/亚硝化应激水平。此外，UDCA可降低癌症干细胞标志物的表达，并减少癌症干细胞的比例。抗氧化剂对氧化应激的抑制作用，可削弱UDCA诱导的癌症干细胞干性降低效应。最后，本研究证实UDCA可诱导线粒体氧化代谢。UDCA并不会改变胰腺腺癌化疗方案中所用化疗药物的疗效。本研究中观察到的UDCA抗肿瘤效应，可能通过构建更强的氧化/亚硝化微环境，从而在胰腺腺癌细胞模型中诱导细胞生长抑制。