Targeting Kca3.1 Channels in Cancer

Abstract

The K_ca3.1 channels, previously designated as IK1 or SK4 channels and encoded by the KCNN4 gene, are activated by a rise of the intracellular Ca²⁺ concentration. These K⁺ channels are widely expressed in many organs and involved in many pathologies. In particular, K_ca3.1 channels have been studied intensively in the context of cancer. They are not only a marker and a valid prognostic tool for cancer patients, but have an important share in driving cancer progression. Their function is required for many characteristic features of the aggressive cancer cell behavior such as migration, invasion and metastasis as well as proliferation and therapy resistance. In the context of cancer, another property of K_ca3.1 is now emerging. These channels can be a target for novel small molecule-based imaging probes, as it has been validated in case of fluorescently labeled senicapoc-derivatives. The aim of this review is (i) to give an overview on the role of K_ca3.1 channels in cancer progression and in shaping the cancer microenvironment, (ii) discuss the potential of using K_ca3.1 targeting drugs for cancer imaging, (iii) and highlight the possibility of combining molecular dynamics simulations to image inhibitor binding to K_ca3.1 channels in order to provide a deeper understanding of K_ca3.1 channel pharmacology. Alltogether, K_ca3.1 is an attractive therapeutic target so that senicapoc, originally developed for the treatment of sickle cell anemia, should be repurposed for the treatment of cancer patients.

Keywords: Kca3.1 channel; Cancer progression; Channel structure; Channel imaging.