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.
Highlights
Pancreatic cancer is quite notorious for its highly aggressive nature with chemotherapy-resistent and radiotherapy-resistant phenotypes and a poor prognosis
To examine whether the cell death-inducing activity of AdipoRon is mediated by AdipoRs, we suppressed the expression of AdipoR1 and AdipoR2 by smallinterfering RNAs (Fig. 1e)
Because it is known that [Ca2+]mt uptake is mediated by mitochondrial Ca2+ uniporter (MCU)[38,39], we examined the effect of the MCU inhibitor Ru360 and found that it blocked AdipoRon-induced cell death (Fig. 3e)
Summary
Pancreatic cancer is quite notorious for its highly aggressive nature with chemotherapy-resistent and radiotherapy-resistant phenotypes and a poor prognosis. The incidence of pancreatic cancer is increasing annually worldwide, becoming the fourth most common cause of cancer-related death[1]. As the majority of pancreatic cancer patients are diagnosed at an inoperable stage[2,3], typically chemotherapy and/or radiotherapy are the primary treatment modalities. Even in patients receiving quality treatment, the overall 5-year relative survival rate is the lowest among cancer-related deaths. To survive such a dire situation, many efforts have been paid to improve local and systemic treatments clinically and to develop more effective and less toxic drugs. APN exerts its effects through the APN receptors AdipoR1 and AdipoR210,11, activating intracellular cytoplasmic signalling molecules, including
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