ADIPORON INCREASES SOCS3 AND SUPPRESSES CYTOKINE MEDIATED STAT3 ACTIVATION TO INHIBIT PANCREATIC CANCER GROWTH
Abstract
Objective: Obesity harbors a systemic chronic inflammatory disorder characterized by increased production and secretion of pro-inflammatory adipokines leptin and IL-6; while exhibiting a decrease in the anti-inflammatory... [ view full abstract ]
Objective: Obesity harbors a systemic chronic inflammatory disorder characterized by increased production and secretion of pro-inflammatory adipokines leptin and IL-6; while exhibiting a decrease in the anti-inflammatory adipokine: adiponectin. The objective of this study was to determine if dysregulation of these factors contributes to activation of mitogenic pathways pancreatic cancer.
Methods: Pancreatic cancer cell lines were treated in vitro with adiponectin or an adiponectin receptor agonist (AdipoRon) and monitored for cellular proliferation and apoptosis. To determine whether AdipoRon could antagonize IL-6 mediated STAT3 activation, PDAC cells were treated with AdipoRon alone or in combination with IL-6 and assessed for pSTAT3 levels. To evaluate whether the PPARy agonist (15d-PGJ2) could synergize with AdipoRon, PDAC cell lines were treated alone or in combination for 12 hours and analyzed by qPCR, western blot, and proliferation. To ascertain whether AdipoRon or 15d-PGJ2 inhibited STAT3 through upregulation of endogenous inhibitors, PIAS and SOCS proteins levels were measured by western blot.
Results: In vitro assessment showed that AdipoRon was highly effective at inhibiting cell proliferation and increasing apoptosis in a dose dependent manner. We now demonstrate that AdipoRon can suppress STAT3 activation in response to cytokine-mediated stimulation such as Leptin or IL-6. Treatment with AdipoRon or with 15d-PGJ2 results in an increased expression of SOCS3, which binds receptor tyrosine kinases and Jak2 to block the downstream phosphorylation of STAT3.
Conclusions: Our results demonstrate that adiponectin receptor activation increases SOCS3 expression, which correlates with suppression of pSTAT3 and decreased proliferation in pancreatic cancer cells.
Authors
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Fanuel Messaggio
(University of Miami – Miller School of Medicine, Miami, Florida, USA)
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Nagaraj Nagathihalli
(University of Miami – Miller School of Medicine, Miami, Florida, USA)
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Nipun Merchant
(University of Miami Leonard M. Miller School of Medicine, Miami, Florida, U.S.A.)
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Michael VanSaun
(University of Miami – Miller School of Medicine, Miami, Florida, USA)
Topic Area
Surgical Oncology
Session
QS-SurgOnc » Quick-Shot Presentations: Surgical Oncology (15:00 - Thursday, 21st September, Lee 404)