tram-34 and Colorectal-Neoplasms

Colorectal cancer (CRC) metastases are the main cause of CRC mortality. Intracellular Ca2+ regulates cell migration and invasion, key factors for metastases. Ca2+ also activates Ca2+-dependent potassium channels which in turn affect Ca2+ driving force. We have previously reported that the expression of the Ca2+ activated potassium channel KCNN4 (SK4) is higher in CRC primary tumors compared to normal tissues. Here, we aimed to investigate the role of SK4 in the physiology of CRC.. SK4 protein expression is enhanced in CRC tissues compared to normal colon tissues, with a higher level of KCNN4 in CRC patients with KRAS mutations. At the cellular level, we found that SK4 regulates the membrane potential of HCT116 cells. We also found that its inhibition reduced store operated Ca2+ entry (SOCE) and constitutive Ca2+ entry (CCE), while reducing cell migration. We also found that the activity of SK4 is linked to resistance pathways such as KRAS mutation and the expression of NRF2 and HIF-1α. In addition, the pharmacological inhibition of SK4 reduced intracellular reactive oxygen species (ROS) production, NRF2 expression and HIF1α stabilization.. Our results suggest that SK4 contributes to colorectal cancer cell migration and invasion by modulating both Ca2+ entry and ROS regulation. Therefore, SK4 could be a potential target to reduce metastasis in KRAS-mutated CRC.

Topics: Calcium; Cell Movement; Colorectal Neoplasms; Databases, Genetic; HCT116 Cells; HT29 Cells; Humans; Intermediate-Conductance Calcium-Activated Potassium Channels; Mutation; Proto-Oncogene Proteins p21(ras); Pyrazoles

Platinum-based drugs such as Cisplatin are commonly employed for cancer treatment. Despite an initial therapeutic response, Cisplatin treatment often results in the development of chemoresistance. To identify novel approaches to overcome Cisplatin resistance, we tested Cisplatin in combination with K. The functional expression of Ca. Cisplatin-resistant CRC cells expressed higher levels of K. As Riluzole, an activator of K

Topics: Animals; Apoptosis; Benzothiazoles; Cell Cycle; Cell Line, Tumor; Cell Survival; Cisplatin; Colorectal Neoplasms; Drug Resistance, Neoplasm; Drug Synergism; ERG1 Potassium Channel; HCT116 Cells; HT29 Cells; Humans; Inhibitory Concentration 50; Intermediate-Conductance Calcium-Activated Potassium Channels; Mice; Potassium Channel Blockers; Pyrazoles; Riluzole