Sajida Ibrahim1, Justine Chaigne2, Hassan Dakik3, Yann Fourbon4, Laetitia Corset3, Thierry Lecomte5, William Raoul4, Maxime Guéguinou6. 1. Université de Tours, EA, 7501 GICC, Tours, France. Electronic address: sajida.ibrahim@mail.mcgill.ca. 2. Université de Tours, EA, 7501 GICC, Tours, France; Université de Tours, Inserm, UMR 1069, Nutrition Croissance et Cancer (N2C), Faculté de Médecine, Tours, France. 3. Université de Tours, EA, 7501 GICC, Tours, France; CNRS ERL 7001 LNOx, Tours, France. 4. Université de Tours, Inserm, UMR 1069, Nutrition Croissance et Cancer (N2C), Faculté de Médecine, Tours, France. 5. Université de Tours, EA, 7501 GICC, Tours, France; CHRU de Tours, Department of Hepato-Gastroenterology and Digestive Oncology, France. 6. Université de Tours, EA, 7501 GICC, Tours, France. Electronic address: maxime.gueguinou@univ-tours.fr.
Abstract
BACKGROUND: 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. RESULTS: 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. CONCLUSION: 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.
BACKGROUND: 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. RESULTS: 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. CONCLUSION: 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.