Indomethacin decreases insulin secretion by reducing KCa3.1 as a biomarker of pancreatic tumor and causes apoptotic cell death

Abstract

Insulinomas originate from pancreatic β cells and it is the most widely known tumor. Indomethacin is a nonsteroidal anti‐inflammatory drug, which is used for blocking the production of some natural substances that cause inflammation and decrease pain. In this study, I aimed to investigate the effects of indomethacin on rat insulinoma INS‐1 cells. The relationship between cell death and insulin metabolism was determined with the administration of indomethacin. The cell viability by WST‐1; the apoptosis and necrosis levels by ELISA kits; malondialdehyde levels by spectrophotometer; and beclin, intracellular insulin, insulin secretion, KCa3.1, insulin receptor (IR), glucose transporter type 2 (GLUT2), activating transcription factor 2 (ATF2), Elk1, c‐Jun, Akt and phosphorylated ATF2, Elk1, c‐Jun, Akt, intracellular betacellulin and betacellulin secretion levels by Western blot analysis investigated. The Ins1, Ins2, IR, GLUT2, ATF2, Elk1, c‐Jun, Akt, and Betacellulin gene expression levels were determined by the real‐time quantitative reverse transcription‐polymerase chain reaction method. Apoptotic cell death was observed with the administration of indomethacin. The insulin secretion and Ins1, Ins2 gene expression levels decreased. The insulin receptor and GLUT2 levels increased, while KCa3.1 (KCNN4) levels decreased with the administration of indomethacin to insulinoma INS‐1 cells. A decrease was observed in the total c‐Jun, phosphorylated ATF2, Elk1, c‐Jun, and Akt levels. Betacellulin secretion levels increased. In insulinoma INS‐1 cells, apoptotic cell death occurred in the following manner: (i) indomethacin might decrease insulin secretion by reducing KCa3.1, (ii) might inactivate the JNK/ERK pathway with the inactivity of transcription factors.

Exploring dual effects of dinutuximab beta on cell death and proliferation of insulinoma

“…In addition, it has been shown that the K + channel KCNN4, which is activated by Ca +2 , plays a key role in cell proliferation and plays an important role in cell migration in the pancreatic ductal adenocarcinoma cell line (Bonito et al, 2016). In our previous study, we showed that after indomethacin was applied to the cells for treatment in insulinoma tumors, the level of KCNN4 decreased and the tumor progression decreased by the death of the cell (Karatug Kacar, 2020). Within the scope of this study, it was observed that the expression of KCNN4 increased, but there was no change in the protein level.…”