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

• Published in: Cell death & disease Vol. 9; no. 8; pp. 804 - 18
• Main Authors: Akimoto, Miho, Maruyama, Riruke, Kawabata, Yasunari, Tajima, Yoshitsugu, Takenaga, Keizo
• Format: Journal Article
• Language: English
• Published: England Springer Nature B.V 23.07.2018; Nature Publishing Group UK
• Subjects: Adiponectin; Antidiabetics; Calcium (mitochondrial); Cell death; Diabetes mellitus; Extracellular signal-regulated kinase; MAP kinase; Mitochondria; Necroptosis; Oral administration; Pancreatic cancer; Superoxide; Tumors
• ISSN: 2041-4889; 2041-4889
• 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 Ca 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.