Amylin-induced cytotoxicity is associated with activation of caspase-3 and MAP kinases

Biol Chem. 2002 Nov;383(11):1751-8. doi: 10.1515/BC.2002.196.


Nanomolar concentrations of human amylin promote death of RINm5F cells in a time- and concentrationdependent manner. Morphological changes of chromatin integrity suggest that cells are predominantly undergoing apoptosis. Human amylin induces significant activation of caspase-3 and strong and sustained phosphorylation of stress-activated protein kinases, c-Jun N-terminal kinase (JNK) and p38, that precedes cell death. Extracellular signal-regulated kinase (ERK) activation was not concomitant with JNK and/or p38 activation. Activation of caspase-3 and mitogen-activated protein kinases (MAPKs) was detected by Western blot analysis. Addition of the MEK1 inhibitor PD 98059 had no effect on amylin-induced apoptosis, suggesting that ERK activation does not play a role in this apoptotic scenario. A correlative inhibition of JNK activation by the immunosuppressive drug FK506, as well as a selective inhibition of p38 MAPK activation by SB 203580, significantly suppressed procaspase-3 processing and the extent of amylin-induced cell death. Moreover, simultaneous pretreatment with both FK506 and SB 203580, or with the caspase-3 inhibitor Ac-DEVD-CHO alone, almost completely abolished procaspase-3 processing and cell death. Thus, our results suggest that amylin-induced apoptosis proceeds through sustained activation of JNK and p38 MAPK followed by caspase-3 activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid / pharmacology*
  • Animals
  • Blotting, Western
  • Caspase 3
  • Caspases / metabolism*
  • Cell Death / drug effects
  • Cell Nucleus / metabolism
  • Cell Nucleus / ultrastructure
  • Cell Survival / drug effects
  • Cells, Cultured
  • Colorimetry
  • Enzyme Activation / drug effects
  • Humans
  • Insulinoma / pathology
  • Islet Amyloid Polypeptide
  • Islets of Langerhans / drug effects*
  • L-Lactate Dehydrogenase / metabolism
  • Mitogen-Activated Protein Kinases / metabolism*
  • Pancreatic Neoplasms / pathology
  • Rats
  • Signal Transduction / drug effects
  • Tetrazolium Salts
  • Thiazoles


  • Amyloid
  • Islet Amyloid Polypeptide
  • Tetrazolium Salts
  • Thiazoles
  • L-Lactate Dehydrogenase
  • Mitogen-Activated Protein Kinases
  • CASP3 protein, human
  • Casp3 protein, rat
  • Caspase 3
  • Caspases
  • thiazolyl blue