Bychkova Solomiia, Bychkov Mykola, Dordević Dani, Rittmann Simon K-M R, Vítězová Monika, Kushkevych Ivan
Department of Human and Animal Physiology, Faculty of Biology, Ivan Franko National University of Lviv, Lviv, Ukraine.
Department of Therapy No. 1, Medical Diagnostic and Hematology and Transfusiology of Faculty of Postgraduate Education, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine.
Front Vet Sci. 2024 Dec 5;11:1480122. doi: 10.3389/fvets.2024.1480122. eCollection 2024.
Colorectal cancer is influenced by genetic mutations, lifestyle factors, and diet, particularly high fat intake, which raises bile acid levels in the intestinal lumen. This study hypothesized that bile acids contribute to tumorigenesis by disrupting ion transport and ATPase activity in the intestinal mucosa. The effects of 3-sulfo-taurolithocholic acid (TLC-S) on ATPase activity were investigated in colorectal cancer samples from 10 patients, using adjacent healthy tissue as controls, and in rodent liver function. ATPase activity was measured spectrophotometrically by determining inorganic phosphorus (P) in postmitochondrial fractions. Ca dynamics were assessed in isolated mouse hepatocytes with fluorescence imaging, and rat liver mitochondria were studied using polarographic methods to evaluate respiration and oxidative phosphorylation. TLC-S increased Na/K ATPase activity by 1.5 times in colorectal cancer samples compared to controls ( ≤ 0.05). In healthy mucosa, TLC-S decreased Mg ATPase activity by 3.6 times ( ≤ 0.05), while Mg ATPase activity in cancer tissue remained unchanged. TLC-S had no significant effect on Ca ATPase activity in healthy colon mucosa but showed a trend toward decreased activity in cancer tissue. In rat liver, TLC-S decreased Ca ATPase and Na/K ATPase activities while increasing basal Mg ATPase activity ( ≤ 0.05). Additionally, TLC-S induced cytosolic Ca signals in mouse hepatocytes, partially attenuated by NED-19, an NAADP antagonist ( ≤ 0.05). TLC-S also reduced the V3 respiration rate of isolated rat liver mitochondria during -ketoglutarate oxidation. These findings suggest that TLC-S modulates ATPase activity differently in cancerous and healthy colon tissues, playing a role in colorectal cancer development. In rat liver, TLC-S affects mitochondrial activity and ATPase function, contributing to altered cytosolic calcium levels, providing insight into the mechanistic effects of bile acids on colorectal cancer and liver function.
结直肠癌受基因突变、生活方式因素和饮食影响，特别是高脂肪摄入，这会提高肠腔内胆汁酸水平。本研究假设胆汁酸通过破坏肠黏膜中的离子转运和ATP酶活性促进肿瘤发生。使用10例患者的结直肠癌样本，并以相邻健康组织作为对照，研究了3-磺基牛磺石胆酸（TLC-S）对ATP酶活性的影响，同时也研究了其对啮齿动物肝功能的影响。通过测定线粒体后组分中的无机磷（P），采用分光光度法测量ATP酶活性。利用荧光成像评估分离的小鼠肝细胞中的钙动力学，并使用极谱法研究大鼠肝线粒体以评估呼吸作用和氧化磷酸化。与对照组相比，TLC-S使结直肠癌样本中的钠钾ATP酶活性增加了1.5倍（P≤0.05）。在健康黏膜中，TLC-S使镁ATP酶活性降低了3.6倍（P≤0.05），而癌组织中的镁ATP酶活性保持不变。TLC-S对健康结肠黏膜中的钙ATP酶活性无显著影响，但在癌组织中显示出活性降低的趋势。在大鼠肝脏中，TLC-S降低了钙ATP酶和钠钾ATP酶活性，同时增加了基础镁ATP酶活性（P≤0.05）。此外，TLC-S在小鼠肝细胞中诱导了胞质钙信号，NAADP拮抗剂NED-19可部分减弱该信号（P≤0.05）。TLC-S还降低了分离的大鼠肝线粒体在α-酮戊二酸氧化过程中的V3呼吸速率。这些发现表明，TLC-S在癌性和健康结肠组织中对ATP酶活性的调节方式不同，在结直肠癌发展中起作用。在大鼠肝脏中，TLC-S影响线粒体活性和ATP酶功能，导致胞质钙水平改变，为胆汁酸对结直肠癌和肝功能的作用机制提供了见解。
