Abstract 439: Tackling oxidative phosphorylation of glioblastoma stem cells through the specific impairment of transmembrane chloride intracellular channel 1

Abstract Solid cancer cells show higher energy and biomolecules requirements compared with healthy cells, making the targeting of cancer metabolic dysfunctions an appealing therapeutic approach. Tackling the tumor metabolism is a daunting task, due to the ability of cancer cells to re-organize their metabolism switching between glycolysis and oxidative phosphorylation. Cancer metabolic plasticity and re-programming is partially supported by altered ionic channels expression and activity. Our laboratory has described the chronic presence transmembrane form of Chloride Intracellular Channel 1 (tmCLIC1) as a marker of malignancy in tumor cells and a possible therapeutic target since it is mainly absent in healthy cells. CLIC1 is described as a metamorphic protein able to shuttle between the cytoplasmic form to a transmembrane conformation. In the present investigation, we show that tmCLIC1 acts as a privileged metformin target in glioblastoma stem-like cells. Metformin is the first-line drug for type 2 diabetes and has been proposed as an antineoplastic drug, but no direct evidence of its’ membrane permeability nor of a specific membrane receptor in cancer cells has been found yet. Here we demonstrate that metformin impairs tmCLIC1 activity by direct and specific binding coordinated by arginine 29. This residue mutation prevents metformin from tmCLIC1 binding and abolishes the drug's effect on glioblastoma cells in 2D and 3D models and its actions on mitochondrial respiration. In vivo experiments in zebrafish embryos and mice orthotopically engrafted with glioblastoma cells and treated with metformin have shown that metformin binding to tmCLIC1 is crucial for its anti-neoplastic effect. Citation Format: Francesca Cianci, Ivan Verduci, Riccardo Cazzoli, Saverio Minucci, Michele Mazzanti. Tackling oxidative phosphorylation of glioblastoma stem cells through the specific impairment of transmembrane chloride intracellular channel 1 abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 439.