Abstract LB_B11: Transmembrane chloride intracellular channel 1 (tmCLIC1) protein as akey regulator of colorectal cancers' aggressiveness

Abstract

Abstract Colorectal cancer is the third leading cause of death in developed countries. Although the huge progresses reached in therapeutically approach, metastases remain the main issue treating colorectal cancer. Ion channels have a prominent role in the acquirement of aggressive phenotype, but most of them are involved in normal physiological processes. Among all the new potential biomarkers, Chloride Intracellular Channel 1(CLIC1) is a promising candidate. As a matter of fact, in physiological homeostasis, CLIC1 is expressed by all cell types as a cytosolic monomer. CLIC1 is a metamorphic protein that coexist in both cytosolic and transmembrane form (tmCLIC1), the latter involved in several pathological states, including cancer. CLIC1 mRNA overexpression was identified in colorectal cancer cells and is related to a poor prognosis. In this scenario, the main aim of the present work is to understand the role of tmCLIC1 in tumorigenesis, invasion, and migration potential of colorectal cancer. We first investigated the level of expression of CLIC1 protein and the activity of its transmembrane form as an ion channel in several colorectal cancer cells at different stage of development. Our results have demonstrated that tmCLIC1 protein expression and activity is proportional to the level of aggressiveness of cells, and here its action is fundamental on cellular proliferation, migration, and invasion. The role of tmCLIC1 activity in colorectal cancer was confirmed also in in vivo models. Experiments performed in zebrafish and mice models have demonstrated that the silencing of CLIC1 results in the impairment of primary tumor development and a strong reduction of distal metastases formation. Moreover, many different metastatic genes are downregulated when CLIC1 protein is absent; in particular, genes related to oxidative stress conditions, typical of cancer cells. As a matter of fact, the peculiar activity of CLIC1 and its binding with glutathione makes this protein essential for redox balance of colorectal cancer cells. Altogether, all the results obtained might be considered a starting point to unveil a mechanism of action that could represent a new milestone in anticancer research. Citation Format: Francesca Cianci, Ivan Verduci, Carlotta Tacconi, Guido Rey, Luca Roz, Alessandro Fantin, Michele Mazzanti. Transmembrane chloride intracellular channel 1 (tmCLIC1) protein as akey regulator of colorectal cancers' aggressiveness [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_B11.