Targeting intra- and extracellular K+ in cancer

With an estimated 9.6 million caused deaths in 2018, cancers represent a leading cause of death worldwide. Hence, it is of utmost importance to understand the molecular and cellular basis of the disease to encounter its onset and progression. Major cancer entities are associated with alterations in the expression and/or function of ion- and especially potassium ion (K+) channels. However, their impact on malignant cell behaviour and the (sub)cellular K+ homeostasis remains largely elusive, as intracellular [K+] measurements and correlations with cellular processes are challenging. We have demonstrated recently that the intracellular K+ concentration is a crucial regulator of cancer cell metabolism via modulating the activity of one of the first and essential enzymes of glycolysis, hexokinase-II. Based on these findings, we postulate, that a better understanding of the molecular mechanisms and protagonists that control the (sub)cellular K+ homeostasis of cancer cells and diverse procedures for manipulating cancer cell K+ gradients have the potential to guide us to novel strategies in the (personalized) diagnosis and therapy of cancerous diseases. By combining murine breast cancer models with our recently developed Genetically Encoded Potassium Ion Indicators to quantify and visualize intra- and extracellular K+ dynamics in primary cancer cells, we aim to obtain the breast cancer cell specific K + profiles. These studies will be corroborated by expression- and functionality analyses of cancer-associated calcium ion (Ca2+) activated K+ (KCa) channels, especially KCa1.1, a frequently cancer-associated K+ channel, using different quantitative and functional assays. Based on these profiles, we aim for a local manipulation of the intracellular [K+] in cancer cells using K+ channel modulators and genetic approaches to modify the cellular K+ profile. This profile will subsequently be correlated with cell metabolism and -malignancy parameters, using genetically encoded sensors and conventional assays. These results obtained in vitro will finally be translated into living animals and verified by the application of novel therapeutic approaches based on our findings. Based on our recent, striking finding of hexokinase-II representing a K+ modulated enzyme, identifying and exploring the importance of the intracellular K+ homeostasis as a key player regulating cancer cell metabolism has the potency to revolutionize our understanding of cellular energy generation pathways. Such identification may contribute to our understanding of yet unknown backgrounds of cancer development and progression. Eventually, novel anti-cancer strategies and therapies may develop and evolve from our findings.