Work

Pimozide Reprograms the Ran GTPase–SCF Axis and Matrix Remodeling Pathways in Breast, Colorectal, and Pancreatic Cancer Models

Year: 2026

Type: article

Abstract: Background: Cancer progression is driven by coordinated dysregulation of intracellular transport, proteostasis, and extracellular matrix remodeling. Therapeutic strategies targeting a single pathway often fail due to tumor adaptability and resistance. Drug repurposing offers a promising approach to identify multi-target anticancer agents with established safety profiles. Pimozide, an FDA-approved antipsychotic drug, has recently emerged as a candidate with potential anticancer activity, although its molecular mechanisms remain incompletely understood. Objectives: This study aimed to investigate the anticancer effects of pimozide across breast, colorectal, and pancreatic cancer models, with a specific focus on its modulation of Ran GTPase signaling, Skp1–Cullin–F-box (SCF) ubiquitin ligase components, and matrix metalloproteinase-2–mediated extracellular matrix remodeling. Methods: Cell viability was assessed using MTT assays in MDA-MB-231, MCF-7, HT-29, and PanC-1 cell lines. Quantitative real-time polymerase chain reaction was employed to evaluate the expression of Ran, MMP2, Cullin1, Rbx1, SKP2, and FBXW10 following pimozide treatment. Molecular docking and MMGBSA analyses were performed to characterize binding interactions between pimozide and selected target proteins. Results: Pimozide induced concentration-dependent cytotoxicity in all tested cell lines with variable IC50 values. Treatment resulted in consistent downregulation of Ran and MMP-2 across cancer types, alongside context-dependent modulation of SCF complex components. Notably, FBXW10 exhibited the strongest binding affinity to pimozide in silico, suggesting functional disruption of ubiquitin-mediated proteostasis. Conclusions: Pimozide exerts anticancer effects through coordinated disruption of nucleocytoplasmic transport, proteostasis regulation, and matrix remodeling. These findings support the repositioning of pimozide as a multi-target anticancer agent and provide a mechanistic foundation for further translational investigation.

Source: Cancers

DOI: 10.3390/cancers18040611