Pathology and Histology Department, Facultad de Ciencias de la Salud, UCAM Universidad Católica San Antonio de Murcia, Campus de los Jerónimos, s/n, 30107, Guadalupe, Murcia, Spain.
Research group "Telomerasa, Envejecimiento y Cáncer," CIBERehd, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Murcia, Spain.
Exp Mol Med. 2020 Feb;52(2):281-292. doi: 10.1038/s12276-020-0389-x. Epub 2020 Feb 20.
Serrated adenocarcinoma (SAC) is more invasive, has worse outcomes than conventional colorectal carcinoma (CRC), and is characterized by frequent resistance to anti-epidermal growth factor receptor (EGFR) and overexpression of fascin1, a key protein in actin bundling that plays a causative role in tumor invasion and is overexpressed in different cancer types with poor prognosis. In silico screening of 9591 compounds, including 2037 approved by the Food and Drug Administration (FDA), was performed, and selected compounds were analyzed for their fascin1 binding affinity by differential scanning fluorescence. The results were compared with migrastatin as a typical fascin1 inhibitor. In silico screening and differential scanning fluorescence yielded the FDA-approved antidepressant imipramine as the most evident potential fascin1 blocker. Biophysical and different in vitro actin-bundling assays confirm this activity. Subsequent assays investigating lamellipodia formation and migration and invasion of colorectal cancer cells in vitro using 3D human tissue demonstrated anti-fascin1 and anti-invasive activities of imipramine. Furthermore, expression profiling suggests the activity of imipramine on the actin cytoskeleton. Moreover, in vivo studies using a zebrafish invasion model showed that imipramine is tolerated, its anti-invasive and antimetastatic activities are dose-dependent, and it is associated with both constitutive and induced fascin1 expression. This is the first study that demonstrates an antitumoral role of imipramine as a fascin1 inhibitor and constitutes a foundation for a molecular targeted therapy for SAC and other fascin1-overexpressing tumors.
锯齿状腺癌（SAC）比传统结直肠癌（CRC）更具侵袭性，预后更差，其特征是经常对表皮生长因子受体（EGFR）产生抗药性，并且 fascin1 过度表达，fascin1 是一种关键的肌动蛋白束状蛋白，在肿瘤侵袭中起因果作用，并在预后不良的不同癌症类型中过度表达。对包括美国食品和药物管理局（FDA）批准的 2037 种化合物在内的 9591 种化合物进行了计算机筛选，并通过差示扫描荧光法分析了选定化合物与 fascin1 的结合亲和力。结果与典型的 fascin1 抑制剂 migrastatin 进行了比较。计算机筛选和差示扫描荧光法得出，FDA 批准的抗抑郁药丙咪嗪是最明显的潜在 fascin1 阻断剂。生物物理和不同的体外肌动蛋白束状实验证实了这一活性。随后的实验研究了丙咪嗪在体外 3D 人组织中对结直肠癌细胞的片状伪足形成和迁移以及侵袭的影响，结果表明丙咪嗪具有抗 fascin1 和抗侵袭活性。此外，表达谱提示丙咪嗪对肌动蛋白细胞骨架的活性。此外，在使用斑马鱼侵袭模型的体内研究中表明，丙咪嗪具有良好的耐受性，其抗侵袭和抗转移活性呈剂量依赖性，并且与组成型和诱导型 fascin1 表达有关。这是第一项证明丙咪嗪作为 fascin1 抑制剂具有抗肿瘤作用的研究，为 SAC 和其他 fascin1 过表达肿瘤的分子靶向治疗奠定了基础。
