Adiponectin receptor agonists inhibit leptin induced pSTAT3 and in vivo pancreatic tumor growth
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// Fanuel Messaggio 1 , Alisha M. Mendonsa 2 , Jason Castellanos 3 , Nagaraj S. Nagathihalli 1 , Lee Gorden 3 , Nipun B. Merchant 1 and Michael N. VanSaun 1 1 Division of Surgical Oncology, Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, USA 2 Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA 3 Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA Correspondence to: Michael N. VanSaun, email: mvansaun@med.miami.edu Keywords: adiponectin, AdipoRon, pancreatic adenocarcinoma, adipokine, STAT3 Received: February 17, 2017 Accepted: July 18, 2017 Published: August 03, 2017 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.
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AdipoRon's beneficial effects have been demonstrated in other non-metabolic conditions such as cancer, systemic sclerosis, depression, anxiety, PTSD, and cerebral ischemia.
“Since then, its beneficial effects have also been demonstrated in other non-metabolic conditions such as cancer [139,140], systemic sclerosis [141], depression [107], anxiety [142], post-traumatic stress disorder [143], and cerebral ischemia [144,145].”
From Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together? (2020) · cites this paper as [139]
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- Authors
- Messaggio, F., Mendonsa, A. M., Castellanos, J., Nagathihalli, N. S., Gorden, L., Merchant, N. B., & VanSaun, M. N.
- Affiliations
- University of Miami (US)
- Vanderbilt University Medical Center (US)
- Corresponding author
- VanSaun, Michael N.
- ORCID
- Venue
- Oncotarget
- Publisher
- Impact Journals, LLC
- Published
- 2017-08-03
- Volume
- 8
- Issue
- 49
- Pages
- 85378-85391
- ISSN
- 1949-2553 (ISSN-L)
- PMC
- PMC5689616
- OpenAlex
- W2742766362
- Cited by
- 60
- References
- 48
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 5 · 2023: 12 · 2022: 8 · 2021: 7 · 2020: 5 · 2019: 11 · 2018: 4
- FWCI
- 4.28
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by
- Locations
- Oncotarget (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- American Cancer Society (IRG-98-277-13, 98-277-13)
- Pancreatic Cancer Action Network
- Vanderbilt University
- University of Miami
- Sylvester Comprehensive Cancer Center, University of Miami Health Systems
- Cancer Research UK
- National Institutes of Health (CA-068485)
- University of California, San Diego
- Leonard M. Miller School of Medicine
- National Cancer Institute (R21CA209536, U01CA143072, R01CA161976, P30CA068485)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK058404)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- adiponectin, AdipoRon, adiponectin receptor agonist, AdipoR1, AdipoR2, leptin, STAT3 signaling, pancreatic ductal adenocarcinoma, adipokines, obesity, apoptosis, tumor cell proliferation, orthotopic tumor growth, cancer therapy
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