RRC ID 54039
Author Akimoto M, Maruyama R, Kawabata Y, Tajima Y, Takenaga K.
Title Antidiabetic adiponectin receptor agonist AdipoRon suppresses tumour growth of pancreatic cancer by inducing RIPK1/ERK-dependent necroptosis.
Journal Cell Death Dis
Abstract 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.
Volume 9(8)
Pages 804
Published 2018-7-23
DOI 10.1038/s41419-018-0851-z
PII 10.1038/s41419-018-0851-z
PMID 30038429
PMC PMC6056513
MeSH 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
IF 6.304
Times Cited 17
Human and Animal Cells PANC-1(RCB2095) MIA Paca2(RCB2094)