Unidad de Morfofisiología, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Avenida de los Barrios 1, Los Reyes Iztacala, 54090, Tlalnepantla, Estado de México, Mexico.
Mol Cell Biochem. 2018 Jan;437(1-2):65-80. doi: 10.1007/s11010-017-3096-8. Epub 2017 Jun 13.
Obesity and type II diabetes mellitus have contributed to the increase of breast cancer incidence worldwide. High glucose concentration promotes the proliferation of metastatic cells, favoring the activation of the plasminogen/plasmin system, thus contributing to tumor progression. The efficient formation of plasmin is dependent on the binding of plasminogen to the cell surface. We studied the effect of ε-aminocaproic acid (EACA), an inhibitor of the binding of plasminogen to cell surface, on proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and plasminogen activation system, in metastatic MDA-MB-231 breast cancer cells grown in a high glucose microenvironment and treated with insulin. MDA-MB-231 cells were treated with EACA 12.5 mmol/L under high glucose 30 mmol/L (HG) and high glucose and insulin 80 nmol/L (HG-I) conditions, evaluating: cell population growth, % of viability, migratory, and invasive abilities, as well as the expression of uPA, its receptor (uPAR), and its inhibitor (PAI-1), by real-time reverse transcription-polymerase chain reaction (RT-PCR) and Western blot, MMP-2 and MMP-9 mRNAs were evaluated by RT-PCR. Markers of EMT were evaluated by Western blot. Additionally, the presence of active uPA was studied by gel zymography, using casein-plasminogen as substrates. EACA prevented the increase in cell population, migration and invasion induced by HG and insulin, which was associated with the inhibition of EMT and the attenuation of HG- and insulin-dependent expression of uPA, uPAR, PAI-1, MMP-2, MMP-9, α-enolase (ENO A), and HCAM. The interaction of plasminogen to the cell surface and plasmin formation are mediators of the prometastasic action of hyperglycemia and insulin, potentially, EACA can be employed in the prevention and as adjuvant treatment of breast tumorigenesis promoted by hyperglycemia and insulin.
肥胖和 2 型糖尿病已导致全球乳腺癌发病率上升。高葡萄糖浓度促进转移细胞的增殖，有利于纤溶酶原/纤溶酶系统的激活，从而促进肿瘤的进展。纤溶酶的有效形成依赖于纤溶酶原与细胞表面的结合。我们研究了 ε-氨基己酸（EACA），一种纤溶酶原与细胞表面结合的抑制剂，对在高葡萄糖微环境中生长并接受胰岛素治疗的转移性 MDA-MB-231 乳腺癌细胞的增殖、迁移、侵袭、上皮-间充质转化（EMT）和纤溶酶原激活系统的影响。在高葡萄糖 30mmol/L（HG）和高葡萄糖加胰岛素 80nmol/L（HG-I）条件下，用 12.5mmol/L EACA 处理 MDA-MB-231 细胞，评估细胞群体生长、存活率、迁移和侵袭能力，以及 uPA、其受体（uPAR）和抑制剂（PAI-1）的表达，通过实时逆转录-聚合酶链反应（RT-PCR）和 Western blot 进行，用 RT-PCR 评估 MMP-2 和 MMP-9 mRNA。通过 Western blot 评估 EMT 标志物。此外，通过使用酪蛋白-纤溶酶原作为底物的凝胶酶谱法研究了活性 uPA 的存在。EACA 可预防 HG 和胰岛素诱导的细胞群体增加、迁移和侵袭，这与 EMT 的抑制以及 HG 和胰岛素依赖性 uPA、uPAR、PAI-1、MMP-2、MMP-9、α-烯醇酶（ENO A）和 HCAM 表达的衰减有关。纤溶酶原与细胞表面的相互作用和纤溶酶的形成是高血糖和胰岛素促进转移作用的介质，潜在地，EACA 可用于预防和辅助治疗由高血糖和胰岛素促进的乳腺癌发生。
