Abstract 2407: Transmembrane chloride intracellular channel 1 (tmCLIC1) protein is a key regulator of colorectal cancers' metastasis

Abstract

Colorectal cancer (CRC) is the third most common tumor worldwide and the fourth cause of cancer-related death. The presence of distal metastasis at the time of the first diagnosis represents a worst prognosis factor for patients’ long-term survival. Therefore, finding new targets to arrest the metastatic process is a main challenge for successful CRC therapy. Our laboratory focused its attention on the Chloride Intracellular Channel 1 (CLIC1), a metamorphic protein able to switch from a cytoplasmic to a transmembrane form associated to ion channel activity. Previous experiments demonstrate that tmCLIC1 functional activity is negligible in normal colon cells, while increases proportionally to CRC cells’ aggressiveness. Moreover, we also reveal that tmCLIC1 supports CRC cells abnormal proliferation rate. Here, we show that tmCLIC1 pharmacological inhibition or its stable downregulation led to a significative reduction of CRC cells migrative and invasive potential, in vitro. To further confirm our hypothesis, we analysed downregulation of metalloproteinase-7 (MMP-7) protein and p38 mitogen-activated protein kinase (MAPK) signalling, both involved in migration and metastatic processes. Moreover, we demonstrate in murine model that CLIC1 knock-down impairs tumor growth and limits cancer cells dissemination. We tried to investigate the alteration of metastatic pathways after CLIC1 silencing. We obtained that many different genes are downregulated when CLIC1 protein is absent; in particular, genes regulated by Reactive Species of Oxygen (ROS) levels. In this scenario, we tried to define the mechanism of action in which CLIC1 is involved. Altogether, all the results obtained in the present work could be considered a starting point to design a new therapeutic strategy to counteract against metastatic colorectal cancer. Citation Format: Francesca Cianci, Ivan Verduci, Valentina Carlini, Carlotta Tacconi, Matteo Ranucci, Alessandro Fantin, Tullio Florio, Michele Mazzanti. Transmembrane chloride intracellular channel 1 (tmCLIC1) protein is a key regulator of colorectal cancers' metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2407.