Abstract
Ursolic acid (UA) possesses various pharmacological activities, such as antitumorigenic and anti-inflammatory effects. In the present study, we investigated the mechanisms underlying the effects of UA against esophageal squamous cell carcinoma (ESCC) (TE-8 cells and TE-12 cells). The cell viability assay showed that UA decreased the viability of ESCC in a dose-dependent manner. In the soft agar colony formation assay, the colony numbers and size were reduced in a dose-dependent manner after UA treatment. UA caused the accumulation of vacuoles and LC3 puncta, a marker of autophagosome, in a dose-dependent manner. Autophagy induction was confirmed by measuring the expression levels of LC3 and p62 protein in ESCC cells. UA increased LC3-II protein levels and decreased p62 levels in ESCC cells. When autophagy was hampered using 3-methyladenine (3-MA), the effect of UA on cell viability was reversed. UA also significantly inhibited protein kinase B (Akt) activation and increased p-Akt expression in a dose-dependent manner in ESCC cells. Accumulated LC3 puncta by UA was reversed after wortmannin treatment. LC3-II protein levels were also decreased after treatment with Akt inhibitor and wortmannin. Moreover, UA treatment increased cellular reactive oxygen species (ROS) levels in ESCC in a time- and dose-dependent manner. Diphenyleneiodonium (an ROS production inhibitor) blocked the ROS and UA induced accumulation of LC3-II levels in ESCC cells, suggesting that UA-induced cell death and autophagy are mediated by ROS. Therefore, our data indicate that UA inhibits the growth of ESCC cells by inducing ROS-dependent autophagy.
Highlights
Esophageal cancer is the eighth most prevalent cancer worldwide and the sixth main cause of cancer-related death, resulting in 456,000 new cases per year [1,2] Esophageal squamous cell carcinoma (ESCC) is predominant in Asian countries, and poor prognoses are often observed after ESCC resection because of its location [3,4,5,6]
We demonstrated that Ursolic acid (UA) induced autophagy in esophageal cancer cells by elevating reactive oxygen species (ROS) levels via the protein kinase B (Akt) signaling pathway
UA significantly induced sub-G1 phase cells in a dose-dependent manner in esophageal cancer cells (TE-8 and TE-12 cells) (Figure 1E). These results indicate that UA induced caspase-dependent cell death in ESCC cells
Summary
Esophageal cancer is the eighth most prevalent cancer worldwide and the sixth main cause of cancer-related death, resulting in 456,000 new cases per year [1,2] Esophageal squamous cell carcinoma (ESCC) is predominant in Asian countries, and poor prognoses are often observed after ESCC resection because of its location [3,4,5,6]. Pentacyclic triterpenoid compounds have been found to display their anticancer properties by altering the levels of reactive oxygen species (ROS), derivatives of oxygen metabolism that are generated under conditions of cellular oxidative stress. Considering that UA-induced autophagy has been implicated in various human cancers, an exploration of the novel signaling pathways relevant to ROS-mediated autophagy would shed light on the development of new therapeutic strategies for ESCC. To address these issues, we investigated whether UA affected ROS levels through autophagy in human ESCC cells. We demonstrated that UA induced autophagy in esophageal cancer cells by elevating ROS levels via the protein kinase B (Akt) signaling pathway. This study showed that UA exerts an antitumorigenic effect on ESCC cells
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