TY - JOUR
T1 - Adiponectin receptor agonists inhibit leptin induced pSTAT3 and in vivo pancreatic tumor growth
AU - Messaggio, Fanuel
AU - Mendonsa, Alisha M.
AU - Castellanos, Jason
AU - Nagathihalli, Nagaraj S.
AU - Gorden, Lee
AU - Merchant, Nipun B.
AU - VanSaun, Michael N.
N1 - Funding Information:
Research was supported by the 2010 Pancreatic Cancer Action Network-AACR Career Development Award, Grant Number 10-20-25-VANS and supported by grant #IRG 98-277-13 from the American Cancer Society.
Funding Information:
Supported by the University of Miami, Miller School of Medicine-Sylvester Comprehensive Cancer Center. NIH #5U01CA143072 supported LG and AMM, NIH CA161976 supported NM and NIH CA209536 supported NN. Core services were provided through Cancer Center Support Grant 5P30 CA068485 and NIH DDRC P30DK058404.
PY - 2017/10/17
Y1 - 2017/10/17
N2 - 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.
AB - 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.
KW - AdipoRon
KW - Adipokine
KW - Adiponectin
KW - Pancreatic adenocarcinoma
KW - STAT3
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U2 - 10.18632/oncotarget.19905
DO - 10.18632/oncotarget.19905
M3 - Article
AN - SCOPUS:85031497845
VL - 8
SP - 85378
EP - 85391
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 49
ER -