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

被引：85

作者：

Akimoto, Miho ^{[1
,4
]}

Maruyama, Riruke ^{[2
]}

Kawabata, Yasunari ^{[3
]}

Tajima, Yoshitsugu ^{[3
]}

Takenaga, Keizo ^{[1
,5
]}

机构：

[1] Shimane Univ, Dept Life Sci, Fac Med, 89-1 Ennya, Izumo, Shimane 6938501, Japan

[2] Shimane Univ, Dept Pathol, Fac Med, 89-1 Ennya, Izumo, Shimane 6938501, Japan

[3] Shimane Univ, Dept Digest & Gen Surg, Fac Med, 89-1 Ennya, Izumo, Shimane 6938501, Japan

[4] Teikyo Univ, Dept Biochem, Sch Med, Itabashi Ku, 2-11-1 Kaga, Tokyo 1738605, Japan

[5] Chiba Canc Ctr, Lab Canc Genet, Res Inst, 666-2 Nitona, Chiba 2608717, Japan

来源：

CELL DEATH & DISEASE | 2018年 / 9卷

关键词：

MITOCHONDRIAL CA2+; PLASMA ADIPONECTIN; INSULIN-RESISTANCE; OBESITY; RISK; APOPTOSIS; ASSOCIATION; ACTIVATION; ANGIOGENESIS; MECHANISMS;

D O I：

10.1038/s41419-018-0851-z

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：18

共 58 条

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