Adiponectin receptor agonists inhibit leptin induced pSTAT3 and in vivo pancreatic tumor growth
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Fanuel Messaggio1, Alisha M. Mendonsa2, Jason Castellanos3, Nagaraj S. Nagathihalli1, Lee Gorden3, Nipun B. Merchant1 and Michael N. VanSaun1
1Division of Surgical Oncology, Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, USA
2Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
3Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Michael N. VanSaun, email: [email protected]
Keywords: adiponectin, AdipoRon, pancreatic adenocarcinoma, adipokine, STAT3
Received: February 17, 2017 Accepted: July 18, 2017 Published: August 03, 2017
Obesity is a significant risk factor for pancreatic cancer, harboring a chronic inflammatory condition characterized by dysregulation of the adipokines, leptin and adiponectin, that in turn alter oncogenic signaling pathways. We and others have shown that leptin promotes the proliferation and an invasive potential of pancreatic cancer cells through STAT3 mediated signaling. However, the role of adiponectin on the tumorigenicity of pancreatic cancer has not been elucidated. Adiponectin represents an important negative regulator of cytokines, which acts through two receptors, ADIPOR1 and ADIPOR2, to elicit pro-apoptotic, anti-inflammatory, and anti-angiogenic responses. We show that the level and expression of both adiponectin receptors are decreased in pancreatic tumors relative to normal pancreatic tissue. In vitro stimulation with adiponectin or a small molecule adiponectin receptor agonist, AdipoRon, increases apoptosis while inhibiting pancreatic cancer cell proliferation, colony formation, and anchorage independent growth. In addition, adiponectin receptor agonism inhibits leptin mediated STAT3 activation. In vivo, treatment of mice with AdipoRon inhibits orthotopic pancreatic tumor growth. These results demonstrate that adiponectin receptor activation is a key regulator of pancreatic cancer growth and AdipoRon provides a rational agent for the development of novel therapeutic strategies for pancreatic cancer.
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