Voltage gated K+ channels (Kv) and integrin receptors in Pancreatic ductal adenocarcinoma (PDAC)

Most of the cancer cells and primary cancers show increased expression of various membrane proteins including ion channels, receptors like EGFR, integrin receptors etc. In this work we characterized the expression of potassium ion channels Kv11.1 (hERG1), EGFR and integrins in pancreatic ductal adenocarcinoma (PDAC). Firstly, our study shows that hERG1 specific blocking decreases the PDAC cell proliferation and anchorage independent colony formation. The study further demonstrates that blocking of hERG1 channels modulates the MAPK signaling pathway most likely mediated by EGFR receptors. In deed hERG1 makes complex formation with EGFR in both PDAC cell lines and primary samples. We then investigated the interactions between hERG1 and integrins. HERG1 and β1 integrins complex formation requires both functional hERG1 channels and activated β1 integrins. In other words, functional blocking of hERG1channels or nonstimulated β1 integrin or both would impair the complex formation between hERG1 and β1. We further demonstrate, using model cell lines, that the interactions between hERG1 and β1 could occur through transmembrane domains. We further investigated the role of hERG1 channels in PDAC cell adhesion, migration and actin cytoskeleton organization. HERG1 specific blocking did not affect the integrin-mediated cell adhesion and focal adhesion formation on ECM proteins. However, when hERG1 was blocked we observed the alterations in filamentous actin organization mediated by β1 integrins. HERG1 blocking specifically induced longer and finely organized f-actin in the cytoplasm, whereas over expression of hERG1 channels induced scattered shorter filaments. Next, we studied the role of hERG1 channels in cell migration and actin dynamics. For this purpose we challenged the role of hERG1 channels in multifactorial dynamic system that is similar to tumor microenvironment. PDAC cells were stimulated with conditioned media of hypoxia activated pancreatic stellate cells and, migration and actin dynamics were quantified. HERG1 blocking decreased the migration rate and interestingly, increased the actin flow (velocity). The increase in velocity was found to be due to increase in diffusion co-efficient of actin flow. Finally, we hypothesize that the hERG1 could mediate the actin dynamics and migration by altering the intracellular calcium concentration ([Ca2+]i). In fact hERG1 blocking decreased the [Ca2+]i by more than two-fold.