Schwarcz Szandra, Kovács Patrik, Nyerges Petra, Ujlaki Gyula, Sipos Adrienn, Uray Karen, Bai Péter, Mikó Edit
Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary.
HUN-REN-UD Cell Biology and Signaling Research Group, Debrecen, 4032, Hungary.
Cell Death Discov. 2024 May 23;10(1):248. doi: 10.1038/s41420-024-02023-1.
Lithocholic acid (LCA) is a secondary bile acid. LCA enters the circulation after bacterial synthesis in the gastrointestinal tract, reaches distantly located cancer cells, and influences their behavior. LCA was considered carcinogenic, but recent studies demonstrated that LCA has antitumor effects. We assessed the possible role of LCA in pancreatic adenocarcinoma. At the serum reference concentration, LCA induced a multi-pronged antineoplastic program in pancreatic adenocarcinoma cells. LCA inhibited cancer cell proliferation and induced mesenchymal-to-epithelial (MET) transition that reduced cell invasion capacity. LCA induced oxidative/nitrosative stress by decreasing the expression of nuclear factor, erythroid 2-like 2 (NRF2) and inducing inducible nitric oxide synthase (iNOS). The oxidative/nitrosative stress increased protein nitration and lipid peroxidation. Suppression of oxidative stress by glutathione (GSH) or pegylated catalase (pegCAT) blunted LCA-induced MET. Antioxidant genes were overexpressed in pancreatic adenocarcinoma and decreased antioxidant levels correlated with better survival of pancreatic adenocarcinoma patients. Furthermore, LCA treatment decreased the proportions of cancer stem cells. Finally, LCA induced total and ATP-linked mitochondrial oxidation and fatty acid oxidation. LCA exerted effects through the farnesoid X receptor (FXR), vitamin D receptor (VDR), and constitutive androstane receptor (CAR). LCA did not interfere with cytostatic agents used in the chemotherapy of pancreatic adenocarcinoma. Taken together, LCA is a non-toxic compound and has antineoplastic effects in pancreatic adenocarcinoma.
石胆酸（LCA）是一种次级胆汁酸。LCA在胃肠道细菌合成后进入循环系统，到达远处的癌细胞，并影响其行为。LCA曾被认为具有致癌性，但最近的研究表明LCA具有抗肿瘤作用。我们评估了LCA在胰腺腺癌中的可能作用。在血清参考浓度下，LCA在胰腺腺癌细胞中诱导了多方面的抗肿瘤程序。LCA抑制癌细胞增殖并诱导间充质-上皮转化（MET），从而降低细胞侵袭能力。LCA通过降低核因子红细胞2样2（NRF2）的表达并诱导诱导型一氧化氮合酶（iNOS）来诱导氧化/亚硝化应激。氧化/亚硝化应激增加了蛋白质硝化和脂质过氧化。用谷胱甘肽（GSH）或聚乙二醇化过氧化氢酶（pegCAT）抑制氧化应激可减弱LCA诱导的MET。抗氧化基因在胰腺腺癌中过表达，抗氧化水平降低与胰腺腺癌患者的更好生存相关。此外，LCA处理降低了癌症干细胞的比例。最后，LCA诱导了总线粒体氧化和ATP相关的线粒体氧化以及脂肪酸氧化。LCA通过法尼醇X受体（FXR）、维生素D受体（VDR）和组成型雄甾烷受体（CAR）发挥作用。LCA不干扰用于胰腺腺癌化疗的细胞抑制剂。综上所述，LCA是一种无毒化合物，在胰腺腺癌中具有抗肿瘤作用。
