Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 85378-85391 |
| Number of pages | 14 |
| Journal | Oncotarget |
| Volume | 8 |
| Issue number | 49 |
| DOIs | |
| State | Published - Oct 17 2017 |
Fingerprint
Keywords
- Adipokine
- Adiponectin
- AdipoRon
- Pancreatic adenocarcinoma
- STAT3
ASJC Scopus subject areas
- Oncology
Cite this
Adiponectin receptor agonists inhibit leptin induced pSTAT3 and in vivo pancreatic tumor growth. / Messaggio, Fanuel; Mendonsa, Alisha M.; Castellanos, Jason; Nagathihalli, Nagaraj; Gorden, Lee; Merchant, Nipun; Vansaun, Michael.
In: Oncotarget, Vol. 8, No. 49, 17.10.2017, p. 85378-85391.Research output: Contribution to journal › Article
}
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
AU - Gorden, Lee
AU - Merchant, Nipun
AU - Vansaun, Michael
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 - Adipokine
KW - Adiponectin
KW - AdipoRon
KW - Pancreatic adenocarcinoma
KW - STAT3
UR - http://www.scopus.com/inward/record.url?scp=85031497845&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85031497845&partnerID=8YFLogxK
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 -