Adiponectin receptor agonists inhibit leptin induced pSTAT3 and in vivo pancreatic tumor growth

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.

AdipoRon Affects Cell Cycle Progression and Inhibits Proliferation in Human Osteosarcoma Cells

“…Recently, the rst oral adiponectin receptor agonist AdipoRon has been identi ed, but its potential pharmacological usage has marginally been explored [22][23][24]. In this regard, initial evidence candidates AdipoR as a potential antineoplastic molecule in various preclinical models, including pancreatic and ovarian cancer [28][29][30].…”

“…In this regard, not completely exhaustive and partially controversial data are available concerning the relationship between AdipoRinduced cell death and apoptosis initiation. Messaggio et al reported that AdipoR increases apoptotic positive cells in human and mouse pancreatic cancer [29], whereas Akimoto et al demonstrate that AdipoR-treated MIA PaCa-2 cells die largely via RIPK1-dependent necroptosis and mitochondrial dysfunction-mediated autophagy [28]. e mechanistic target of rapamycin (mTOR) is a pivotal prosurvival signaling pathway that negatively affects autophagy and self-digesting independent cell death processes [41,48].…”

“…e mechanistic target of rapamycin (mTOR) is a pivotal prosurvival signaling pathway that negatively affects autophagy and self-digesting independent cell death processes [41,48]. Several evidence proves that AdipoR phosphorylates the upstream mTORC1 blocker AMP-activated protein kinase (AMPK); however, the resulting impact on mTORC1 still remains unpredictable [28][29][30][42][43][44]. Our findings further confirm a not univocal and direct mTORC1 modulation mediated by AdipoR; indeed, while AdipoR causes a complete mTORC1 downstream target p70S6K inactivation in Saos-2, an unchanged trend has been detected in U2OS cells.…”

“…Over the past few years, AdipoR is emerging as a possible candidate for the treatment of different pathological conditions, including metabolic, cardiovascular, and psychiatric disorders, specifically comorbidity between depression and obesity [22][23][24]. According to the antitumor effects observed in response to Acrp30 [25,26] and the opposite relation between its circulating levels and risk of developing cancer [27], initial reports have also investigated the possible anticancer role of AdipoRon in preclinical models, especially in pancreatic and ovarian cancer [28][29][30]. To our knowledge, no evidence has been published yet concerning the possible antiproliferative properties of AdipoR and more in general of Acrp30 in OS.…”

Examining the Potential of Developing and Implementing Use of Adiponectin-Targeted Therapeutics for Metabolic and Cardiovascular Diseases

“…AdipoRON effectively improved insulin sensitivity and restored glucose homeostasis via the activation of AdipoR1-AMPK-PGC1α and AdipoR2-PPARα signaling pathways (162). AdipoRON treatment also mimicked adiponectin's established anti-diabetic effects (163) and ability to enhance cellular capacity for mitigating oxidative-stress (162,164), enhancing lipid/glucose oxidation in mitochondria (162,164), anti-inflammatory responses (162,(164)(165)(166)(167), lifeprolonging effect (162,163), anti-cancer effects (168,169), procell survival and anti-apoptotic effect (170,171), neuronal- (172,173), reno- (174,175), and cardio-/vascular-protective effects (165,(176)(177)(178)(179). However, exciting AdipoRON research in animal models has not been translated to establishment of a drug for human use and the search continues for additional small molecule AdipoR agonists which have little or no toxicity.…”