InterTask · Therapeutic molecules and druggable sites to suppress aberrant ion channel activity in cancer.

Therapeutic molecules and druggable sites to suppress aberrant ion channel activity in cancer.

Ion channels are membrane proteins, i.e. cellular components, involved in a variety of physiological processes and they have been deeply studied for their role in excitable cells and transmission of the electric signal. Building on these early studies, it has been possible to correlate ion channels malfunctions with many pathological conditions affecting the nervous and cardiac systems. More recently, evidences accumulated highlighting a role of ion channels in cancer. Hence ion channels have emerged as pharmacological targets to contrast angiogenesis and tumor growth. The present study focused on a class of proteins known as K2P channels. They have attracted a lot of interest for their ability to respond to a large number of chemical and physical cues in the cell and malfunction of K2Ps have been linked to many pathological conditions such as depression, autoimmune and degenerative diseases, mental retardation, migraine, ischemia, epilepsy and tumorigenesis. The subject of this study, TASK-3 (TWIK-related Acid-Sensitive K+ channel), has been also implicated in cancer for its aberrant presence with a frequency of 44% among the breast cancer and it was also found in 35% of lung cancers. This evidence strongly supports the idea that TASK-3 may constitute an important therapeutic target in malignancies in which the ion channel is aberrantly expressed. The development of a novel TASK-3 specific therapeutic tool, which could be used to treat tumors as well as to unravel the underlining contribution of TASK-3 at the molecular level, heavily relies on structural and functional information on the channel, especially in complex with partners known to reduce or modulate its activity. The overall objectives of the study consisted of approaching TASK-3 at the molecular level, by studying the three-dimensional structure of this cellular component and to develop therapeutic tools based on antibodies to control its presence in cancer phenotypes. Another objective of the proposed research was to directly control the presence of the protein by acting on other cellular components that directly interact with it. The approach was to understand the interaction between the two components to have a starting point for the design of therapeutics capable of controlling the presence of the TASK-3 protein in different organs. The execution of the study let to achieve most of the first objective with the determination of the structure of TASK-3 together with an IgG that recognizes the channel and cause its internalization in breast cancer metastasis. The second objective was only partially achieved and more progress will be required to understand the molecular basis on TASK-3 presence due to its interaction with other cellular components.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз