Abstract
Although substantial studies on peroxisome proliferator-activated receptor γ (PPARγ) have focused on the mechanisms by which PPARγ regulates glucose and lipid metabolism, recent reports have suggested that PPARγ shows tumorigenic or antitumorigenic effects. The roles and mechanisms of PPARγ activation in esophageal cancer remain unclarified. EC109 and TE10 esophageal cancer cells were treated with 0, 10, 20 and 40 mM of PPARγ agonist rosiglitazone (RGZ) for 24, 48, and 72 h, and the cell viability and apoptosis were detected using methyl thiazolyl tetrazolium (MTT) assay and Flow cytometric (FCM) analysis, respectively. Moreover, the effects of inhibition of PPARγ by antagonist or specific RNA interference on cell viability, apoptosis, the Toll-like receptor 4 (TLR4) and mitogen-activated protein kinase (MAPK) pathways were evaluated. Additionally, the effect of TLR4 signaling on the MAPK pathway, cell viability and apoptosis was assessed. The results showed that RGZ suppressed proliferation and induced apoptosis of esophageal cancer cells, which could be partly restored by inactivation of PPARγ. RGZ suppressed the MAPK and TLR4 pathways, and the inhibitory effect could be counteracted by PPARγ antagonist or specific RNA interference. We also suggested that MAPK activation was regulated by the TLR4 pathway and that blocking the TLR4 and MAPK pathways significantly suppressed proliferation and induced apoptosis of esophageal cancer cells. In conclusion, our data suggested that activation of PPARγ suppressed proliferation and induced apoptosis of esophageal cancer cells by inhibiting TLR4-dependent MAPK pathway.
Highlights
Esophageal cancer is an aggressive malignancy, with an estimated 455,800 new esophageal cancer cases and 400,200 deaths worldwide in 2012 [1]
These inhibitory effects of RGZ were TLR4dependent, as the inhibitory effects were not observed in Toll-like receptor 4 (TLR4)- and MyD88-knockdown cells (Figure 5). These results indicate that inhibition of mitogen-activated protein kinase (MAPK) pathway by Peroxisome proliferator-activated receptor γ (PPARγ) agonist requires TLR4
Though the roles of PPARγ in cancer therapy are debatable, accumulating evidence suggested that activation of PPARγ by agonists exerts an inhibitory effect on cancer cells [32]
Summary
Esophageal cancer is an aggressive malignancy, with an estimated 455,800 new esophageal cancer cases and 400,200 deaths worldwide in 2012 [1]. Esophageal cancer is the eighth most common malignancy, and the sixth most common cause of death from cancer worldwide. About 80% of the cases occur in developing countries. It was estimated that about 375,000 Chinese died from esophageal cancer in 2015 [2]. The most common cancerrelated complication of esophageal cancer is swallowing difficulty with the cancer development, resulting in malnutrition, pain and lower quality of life [3, 4]. Long-term survival remains poor with 5-year survival rates of 15-25%, underscoring the urgency to develop novel treatment strategies [5]
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