Abstract
Gastric cancer represents a malignant type of cancer worldwide. Tanshinone IIA (Tan IIA), a pharmacologically active component isolated from the rhizome of the Chinese herb Salvia miltiorrhiza Bunge (Danshen), has been reported to possess an anti-cancer effect in gastric cancer. However, its mechanisms are still not fully understood. In the present study, we found that Tan IIA induced ferroptosis in BGC-823 and NCI-H87 gastric cancer cells. Tan IIA increased lipid peroxidation and up-regulated Ptgs2 and Chac1 expression, two markers of ferroptosis. Ferrostatin-1 (Fer-1), an inhibitor of lipid peroxidation, inhibited Tan IIA caused-lipid peroxidation and Ptgs2 and Chac1 expression. In addition, Tan IIA also up-regulated p53 expression and down-regulated xCT expression. Tan IIA caused decreased intracellular glutathione (GSH) level and cysteine level and increased intracellular reactive oxygen species (ROS) level. p53 knockdown attenuated Tan IIA-induced lipid peroxidation and ferroptosis. Tan IIA also induced lipid peroxidation and ferroptosis in BGC-823 xenograft model, and the anti-cancer effect of Tan IIA was attenuated by Fer-1 in vivo. Therefore, Tan IIA could suppress the proliferation of gastric cancer via inducing p53 upregulation-mediated ferroptosis. Our study have identified a novel mechanism of Tan IIA against gastric cancer, and might provide a critical insight into the application of Tan IIA in gastric cancer intervention.
Highlights
Gastric cancer is the fifth most common cancer in the world and the second leading cause of cancer deaths
These results shows that Tan Tanshinone IIA (IIA) could induce cell death in BGC-823 and NCI-H87 gastric cancer cells
The cell death caused by Tanshinone IIA (Tan IIA) was deservedly attenuated by Fer-1 (Figure 2J). These results suggest that Tan IIA causes cell death of BGC-823 and NCI-H87 gastric cancer cells via inducing ferroptosis
Summary
Gastric cancer is the fifth most common cancer in the world and the second leading cause of cancer deaths. 1 million new diagnoses are made every year. More than one-third of the world total occurs in China [1]. It is estimated that the 5-year survival rate of gastric cancer is lower than 20% in patients [2]. There are four defined subtypes of gastric cancer in the clinic, namely, papillary, mucinous, tubular, and signet ring cell cancers. The major risk factors of the occurrence and development of gastric carcinoma include gastroesophageal reflux disease, infection with Helicobacter pylori, dietary factors, and obesity [3]. The understanding of pathology of gastric cancer is increasing, conventional surgery, radiotherapy, and chemotherapy remain the primary therapeutic strategies [4]
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