CELL CYCLE AND MIGRATION CONTROL IN PROSTATE AND COLON CANCER CELLS BY CLIC1 PROTEIN

The intracellular chloride channel 1 (CLIC1) is a metamorphic protein, belonging to a recently discovered and still largely unexplored ion channel family. It displays the unique characteristic of being expressed both in a cytoplasmic and in a transmembrane form, the latter able to form a chloride selective ion channel. One of the main factors known to regulate this membrane insertion is the increase of oxidative level of the cells. If on one hand, the transient CLIC1 functional expression in the membrane could mediate several physiological cell responses, on the other hand, its chronic membrane translocation can lead to severe pathological conditions, including cancer. In particular two tumors, prostate cancer (PCa) and colon cancer (CRC), are characterized by elevated oxidative level and growing scientific evidence have suggested the involvement of CLIC1 in the tumorigenesis of these diseases. PCa and CRC are two of the most diffuse cancers and a leading cause of tumor fatality worldwide. Detecting the disease in a very early stage and finding a treatment able to prevent metastasis are critical clinical challenges to achieve a successful treatment for these malignancies. This thesis was focused in the direction of understanding the possible role of CLIC1 in the development and progression of PCa and CRC. Results obtained have shown that CLIC1 functional expression in plasma membrane occurs selectively in malignant cells, compared to benign or normal cells. Moreover, it has been demonstrated that CLIC1 membrane chloride current promotes proliferation, cell cycle progression from G1 to S phase and migration of cancer cells. All these findings suggest that CLIC1 may actively contribute to development of PCa and CRC and their progression towards a more aggressive form. It can be reasonably hypothesize that elevated oxidative levels present in cancer cells compared to normal cells cause the chronic overexpression of CLIC1 in the plasma membrane only of malignant cells. Therefore, targeting this protein could make it possible to hit selectively the tumor cells without damaging their normal counterpart. In this scenario, CLIC1 appears not only as a promising pharmacological target but also as a suitable biomarker. The only effective inhibitor of CLIC1 activity to date identified is highly toxic in vivo. For this reason, finding other compounds able to specifically block the channel but causing negligible side effects is necessary. In light with this purpose, our laboratory has recently proposed the anti-diabetic drug metformin as CLIC1 channel blocker. Results obtained have demonstrated that metformin displays a significant antitumoral activity on PCa and CRC cells, inhibiting both cell proliferation and migration. This anti-neoplastic effect is dependent on the inhibition of CLIC1 channel together with other intracellular targets. Overall these findings provide new support on the antineoplastic role of metformin and encourage the research of more specific and more effective compounds for CLIC1 channel, in order…