u-0126 and Insulinoma

Apoptotic death of pancreatic β cells is a major cause of type 2 diabetes mellitus (T2D) progression. Two isoforms of pyruvate kinase, PKM1 and PKM2, have been reported to participate in cell death in several cell types; however, little is known about their causal pathways in pancreatic β-cell death. We examined whether the suppression of PKM1 or PKM2 affects endoplasmic reticulum (ER) stress-induced apoptosis in a pancreatic β-cell line, MIN6, and Beta-TC-6 and found that knockdown of PKM1, but not of PKM2, leads to the induction of ER stress-induced apoptosis in these cells. We also investigated the mechanism by which PKM1 inhibits ER stress-induced apoptosis. We confirmed that PKM1 interacts with A-Raf, an upstream regulator of the MEK/ERK pathway, and that this interaction contributes to MEK1 phosphorylation by A-Raf. PKM1 knockdown suppresses the phosphorylation of MEK, ERK, and caspase-9 (Thr125), which is phosphorylated by the MEK/ERK pathway, thereby inhibiting the cleavage and activation of caspase-9. Thus, PKM1 knockdown activates the caspase-9/caspase-3 pathway under ER stress conditions and leads to apoptosis.

Topics: Adenosine Triphosphate; Animals; Apoptosis; Butadienes; Carrier Proteins; Caspase 3; Caspase 9; Cell Line, Tumor; eIF-2 Kinase; Endoplasmic Reticulum Stress; Endoribonucleases; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Gene Knockdown Techniques; Insulinoma; MAP Kinase Signaling System; Membrane Proteins; Mice; Mitogen-Activated Protein Kinase Kinases; Models, Biological; Nitriles; Phosphorylation; Protein Binding; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins A-raf; Pyruvic Acid; Thyroid Hormone-Binding Proteins; Thyroid Hormones