Targeting Kca3.1 Channels in Cancer

Abstract

The Kca3.1 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, Kca3.1 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 Kca3.1 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 Kca3.1 channels in cancer progression and in shaping the cancer microenvironment, (ii) discuss the potential of using Kca3.1 targeting drugs for cancer imaging, (iii) and highlight the possibility of combining molecular dynamics simulations to image inhibitor binding to Kca3.1 channels in order to provide a deeper understanding of Kca3.1 channel pharmacology. Alltogether, Kca3.1 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.

Potassium channels: Novel targets for tumor diagnosis and chemoresistance

“…Small molecule and channel-targeting antibodies can be used for imaging KCa3.1 channels in vitro and in vivo . Because KCa3.1 channel expression has predictive potential for prognosis and patient survival in different tumor entities, imaging probes targeting KCa3.1 channel expression can serve as necessary diagnostic tools ( 89 ).…”

Ion Channels as Potential Tools for the Diagnosis, Prognosis, and Treatment of HPV-Associated Cancers

“…In head and neck cancer, the inhibition of programmed death receptor alpha 1 (αPD-1) increases the fluxes of KCNN4 and Kv1.3 channel activity, thus improving the immune function [131]. Likewise, pembrolizumab, which is a humanized monoclonal antibody with high specificity towards PD-1, has been used in the treatment of several malignancies, including head and neck cancer [182], and increases KCNN4 channel activity and CD8 T-cell chemotaxis (Table 2) [132].…”

Plasma membrane SK2 channel activity regulates migration and chemosensitivity of high‐grade serous ovarian cancer cells

“…SK2 channels were also identified in intracellular compartments, such as mitochondria, the endoplasmic reticulum (ER), or vesicles, and notably controlling cell death [17][18][19][20]. Although there is little information on SKCa channels in cancers, these channels participated in cell proliferation and cell migration [21][22][23]. Our laboratory has described the role of plasma membrane SK3 in breast, melanoma, prostate, and colon cancer cell migration in vitro and in breast cancer metastasis in vivo [14 (p. 20), 15,21,24].…”