Small-molecule COH-SR4 inhibits adipocyte differentiation via AMPK activation

Figarola, James L.; Rahbar, Samuel

doi:10.3892/ijmm.2013.1313

Cited by 36 publications

(32 citation statements)

References 49 publications

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“…Moreover, siRNA-mediated AMPK knockdown significantly reversed the cytotoxic effects of SR4 on HepG2. We observed similar inhibitory effects of SR4 on mTOR in previous studies with 3T3-L1 adipocyte (33) and lung cancer cells (31) using both Compound C and AMPK knockdown. In the lung cancer studies, similar AMPK knockdown decreased the cytotoxic effects of SR4, concomitant with decreased inhibition of mTOR signaling.…”

Section: Discussionsupporting

confidence: 68%

“…SR4 is a multitargeting agent with no overt toxicity for normal tissues when administered orally, as observed in our previous experiments. In the present study, we investigated the molecular mechanisms of SR4-induced cell death in HepG2 cells in relation to mitochondrial dysfunction and bioenergetics, which we hypothesize as upstream signals for its anticancer properties based on earlier observations of indirect AMPK activation (33). We found that SR4 dose-and time-dependently increased the mitochondrial respiration (increased OCR) and promoted collapse of mitochondrial potential in both intact HepG2 cells and isolated mouse liver mitochondria.…”

Section: Discussionmentioning

confidence: 91%

“…The lead compound SR4 showed promising antitumor activities in in vitro cell cultures and in vivo animal xenograft models, including leukemia, lung cancers, and melanoma (30 -32). SR4 was shown to indirectly activate the energy-sensing enzyme AMPK (33), but the mechanism remained unknown. In this study, we identify a novel mitochondrial uncoupling property of SR4, which is directly associated with its anticancer properties.…”

Section: Hepatocellular Carcinoma (Hcc)mentioning

confidence: 99%

“…In addition, cellular levels of AMP, ATP, and ADP were measured 1 h after treatment as described previously (33).…”

Section: Cellular Atp Amp and Adp Measurementmentioning

confidence: 99%

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SR4 Uncouples Mitochondrial Oxidative Phosphorylation, Modulates AMP-dependent Kinase (AMPK)-Mammalian Target of Rapamycin (mTOR) Signaling, and Inhibits Proliferation of HepG2 Hepatocarcinoma Cells

Figarola

Singhal

Tompkins

et al. 2015

Journal of Biological Chemistry

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Mitochondrial oxidative phosphorylation produces most of the energy in aerobic cells by coupling respiration to the production of ATP. Mitochondrial uncouplers, which reduce the proton gradient across the mitochondrial inner membrane, create a futile cycle of nutrient oxidation without generating ATP. Regulation of mitochondrial dysfunction and associated cellular bioenergetics has been recently identified as a promising target for anticancer therapy. Here, we show that SR4 is a novel mitochondrial uncoupler that causes dose-dependent increase in mitochondrial respiration and dissipation of mitochondrial membrane potential in HepG2 hepatocarcinoma cells. These effects were reversed by the recoupling agent 6-ketocholestanol but not cyclosporin A and were nonexistent in mitochondrial DNA-depleted HepG2 cells. In isolated mouse liver mitochondria, SR4 similarly increased oxygen consumption independent of adenine nucleotide translocase and uncoupling proteins, decreased mitochondrial membrane potential, and promoted swelling of valinomycin-treated mitochondria in potassium acetate medium. Mitochondrial uncoupling in HepG2 cells by SR4 results in the reduction of cellular ATP production, increased ROS production, activation of the energy-sensing enzyme AMPK, and inhibition of acetyl-CoA carboxylase and mammalian target of rapamycin signaling pathways, leading to cell cycle arrest and apoptosis. Global analysis of SR4-associated differential gene expression confirms these observations, including significant induction of apoptotic genes and down-regulation of cell cycle, mitochondrial, and oxidative phosphorylation pathway transcripts at 24 h post-treatment. Collectively, our studies demonstrate that the previously reported indirect activation of AMPK and in vitro anticancer properties of SR4 as well as its beneficial effects in both animal xenograft and obese mice models could be a direct consequence of its mitochondrial uncoupling activity. Hepatocellular carcinoma (HCC)2 is the most common and severe form of liver cancer, accounting for about 80 -90% of primary liver cancers and 5% of all human cancers. More than 600,000 deaths are attributed to HCC every year with 2:1 ratio for men versus women (1, 2). HCC is a primary cancer of hepatocytes that most typically occurs in the setting of known risk factors, including cirrhosis and chronic hepatitis B virus or hepatitis C virus infections (2, 3), although recently, several lines of evidence suggest that type 2 diabetes is also an independent risk factor for HCC development (4). HCC is an aggressive tumor and represents a major health problem as its incidence is increasing. Systemic chemotherapies have proven ineffective against advanced HCC, so it typically leads to death within 6 -20 months (5). Hepatocarcinogenesis is a multistep process involving inflammation, hyperplasia, and dysplasia that finally leads to malignant transformation. In recent years, mitochondria have been found to provide a novel targeting site for new anticancer drugs (known as "mitocans") that ca...

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 91%

Section: Hepatocellular Carcinoma (Hcc)mentioning

confidence: 99%

“…In addition, cellular levels of AMP, ATP, and ADP were measured 1 h after treatment as described previously (33).…”

Section: Cellular Atp Amp and Adp Measurementmentioning

confidence: 99%

See 2 more Smart Citations

SR4 Uncouples Mitochondrial Oxidative Phosphorylation, Modulates AMP-dependent Kinase (AMPK)-Mammalian Target of Rapamycin (mTOR) Signaling, and Inhibits Proliferation of HepG2 Hepatocarcinoma Cells

Figarola

Singhal

Tompkins

et al. 2015

Journal of Biological Chemistry

Self Cite

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“…Inhibition of adipocyte differentiation to adult fat storing cells has been targeted by several obesity treatment strategies for the development of antiobesity and antidiabetic drugs. It was reported that COH-SR4, an aromatic urea derivative, inhibits adipocyte differentiation in 3T3-L1 cells [59]. The effect mainly occurs at the early phase of differentiation through the inhibition of mitotic clonal expansion and cell cycle arrest at the G1/S phase transition.…”

Section: T3-l1mentioning

confidence: 99%

Activators of AMPK: Not Just for Type II Diabetes

2014

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Recent discoveries of AMPK activators point to the large number of therapeutic candidates that can be transformed to successful designs of novel drugs. AMPK is a universal energy sensor and influences almost all physiological processes in the cells. Thus, regulation of the cellular energy metabolism can be achieved in selective tissues via the artificial activation of AMPK by small molecules. Recently, special attention has been given to direct activators of AMPK that are regulated by several nonspecific upstream factors. The direct activation of AMPK, by definition, should lead to more specific biological activities and as a result minimize possible side effects.

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Dapagliflozin prevents abdominal visceral and subcutaneous adipose tissue dysfunction in the insulin‐resistant canine model

Kabir

Bergman

Porter

et al. 2023

Obesity

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Objective Sodium‐glucose cotransporter 2 inhibitors (SGLT2i) promote urinary glucose excretion, induce weight loss, and reduce fat accumulation. The effects of the SGLT2i dapagliflozin (DAPA) on subcutaneous (SC) and visceral (VIS) adipose tissue function remain unclear. The objective of this study is to evaluate SC and VIS adipose tissue function in an insulin‐resistant canine model. Methods A total of 12 dogs were fed a high‐fat diet (HFD) for 6 weeks and then were given a single low dose of streptozotocin (18.5 mg/kg) to induce insulin resistance. Animals were then randomized and exposed to DAPA (n = 6, 1.25 mg/kg) or placebo (n = 6) once per day for 6 weeks while remaining on the HFD. Results DAPA prevented further weight gain induced by the HFD and normalized fat mass. DAPA reduced fasting glucose and increased free fatty acids, adiponectin, and β‐hydroxybutyrate. DAPA reduced adipocyte diameter and cell distribution. Furthermore, DAPA increased genes associated with beiging, lipolysis, and adiponectin secretion and the expression of the adiponectin receptor ADR2, in SC and VIS adipose tissue. DAPA increased AMP‐activated protein kinase activity and maximal mitochondrial respiratory function, especially in the SC depot. Furthermore, DAPA reduced cytokines and ceramide synthesis enzymes in SC and VIS depots. Conclusions For the first time, to our knowledge, we identify mechanisms by which DAPA enhances adipose tissue function in regulating energy homeostasis in an insulin‐resistant canine model.

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Small-molecule COH-SR4 inhibits adipocyte differentiation via AMPK activation

Cited by 36 publications

References 49 publications

SR4 Uncouples Mitochondrial Oxidative Phosphorylation, Modulates AMP-dependent Kinase (AMPK)-Mammalian Target of Rapamycin (mTOR) Signaling, and Inhibits Proliferation of HepG2 Hepatocarcinoma Cells

SR4 Uncouples Mitochondrial Oxidative Phosphorylation, Modulates AMP-dependent Kinase (AMPK)-Mammalian Target of Rapamycin (mTOR) Signaling, and Inhibits Proliferation of HepG2 Hepatocarcinoma Cells

Activators of AMPK: Not Just for Type II Diabetes

Dapagliflozin prevents abdominal visceral and subcutaneous adipose tissue dysfunction in the insulin‐resistant canine model

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