Abstract

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.

Highlights

  • Tumor metastasis is the leading cause of cancer-related deaths[1]

  • Our group identified fascin[1] as overexpressed in serrated adenocarcinoma (SAC), a WHO-recognized histological subtype of colorectal carcinoma (CRC), which is characterized by worse prognosis[6] and a more active invasive front as evidenced by a higher occurrence of tumor budding[7], E-cadherin loss, and more frequent KRAS or BRAF mutations compared with conventional CRC8–10

  • A tricyclic antidepressant (TCA), gave a high score in the bioinformatics analysis, which was subsequently validated in vitro by Thermofluor, fluorescence titration experiments, and Transmission electron microscopy (TEM)

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Summary

Introduction

Tumor metastasis is the leading cause of cancer-related deaths[1]. Cell migration and invasion are fundamental features of metastatic cancer cells and involve actin cytoskeleton rearrangement, leading to the formation of protrusive structures, such as filopodia, lamellipodia, and invadopodia, that contribute to cancer cell motility[2].Fascin[1] is an actin filament (F-actin) bundling protein that plays an important role in the formation of protrusive structures and is poorly expressed or absent in most normal epithelia but upregulated in many human carcinomas, with a crucial role in tumor progression, invasion, and metastasis[3,4]. Tumor metastasis is the leading cause of cancer-related deaths[1]. Cell migration and invasion are fundamental features of metastatic cancer cells and involve actin cytoskeleton rearrangement, leading to the formation of protrusive structures, such as filopodia, lamellipodia, and invadopodia, that contribute to cancer cell motility[2]. Fascin[1] is an actin filament (F-actin) bundling protein that plays an important role in the formation of protrusive structures and is poorly expressed or absent in most normal epithelia but upregulated in many human carcinomas, with a crucial role in tumor progression, invasion, and metastasis[3,4]. Numerous studies have implicated fascin[1] as a potential therapeutic target and biomarker for aggressive carcinomas[4,5]. Migrastatin and its macroketone analogs have been found to efficiently

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