Antidiabetic adiponectin receptor agonist AdipoRon suppresses tumour growth of pancreatic cancer by inducing RIPK1/ERK-dependent necroptosis

Cell Death Dis. 2018 Jul 23;9(8):804. doi: 10.1038/s41419-018-0851-z.


The association between lower circulating adiponectin (APN) levels and the development of pancreatic cancer has been reported. However, the effect of APN on the growth and survival of pancreatic cancer cells remains elusive. Here, we investigate the effects of the anti-diabetic APN receptor (AdipoR) agonist AdipoRon and APN on human pancreatic cancer cells. We found that AdipoRon, but not APN, induces MIAPaCa-2 cell death, mainly through necroptosis. Mechanistically, although both AdipoRon and APN activate AMPK and p38 MAPK in an AdipoR-dependent manner that elicits survival signals, only AdipoRon induces rapid mitochondrial dysfunction through mitochondrial Ca2+ overload, followed by superoxide production via RIPK1 and ERK1/2 activation. Oral administration of AdipoRon suppresses MIAPaCa-2 tumour growth without severe adverse effects and kills cancer cells isolated from patients with pancreatic cancer. Thus, AdipoRon could be a therapeutic agent against pancreatic cancer as well as diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Calcium / metabolism
  • Calcium Channels / chemistry
  • Calcium Channels / genetics
  • Calcium Channels / metabolism
  • Cell Line, Tumor
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Humans
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Piperidines / pharmacology*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
  • Receptors, Adiponectin / agonists*
  • Signal Transduction / drug effects
  • Superoxides / metabolism
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • AdipoRon
  • Calcium Channels
  • Piperidines
  • RNA, Small Interfering
  • Receptors, Adiponectin
  • mitochondrial calcium uniporter
  • Superoxides
  • RIPK1 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Calcium