Gambogic acid (GA) is a natural xanthonoid secreted by Garcinia hanburyi tree. It possesses anti-cancer activity in various types of cancers. In gastric cancer, it inhibits cell proliferation through increasing apoptosis. However, whether necroptosis is involved in the GA-induced proliferation inhibited in gastric cancer is unknown. In the present study, we found that RIPK1 specific inhibitor necrostatin-1 (Nec-1) attenuated GA-induced proliferation inhibition. GA treatment increased the phosphorylation of necroptosis-related proteins, RIPK1, RIPK3, and MLKL, and their interactions to form the necrosome complex. The effector protein Drp-1 was dephosphorylated by GA treatment. Inhibition of necroptosis by different inhibitors and PGAM5 knockdown attenuated GA-induced cell death in gastric cancer cell lines, thereby attenuating GA-caused cell proliferation inhibition. All the data supported the conclusion that GA could inhibit gastric cancer cell proliferation by inducing necroptosis.

中文翻译：

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藤黄酸通过坏死性凋亡抑制胃癌细胞增殖

藤黄酸（GA）是藤黄树分泌的天然黄酮类化合物。它对多种癌症具有抗癌活性。在胃癌中，它通过增加细胞凋亡来抑制细胞增殖。然而，坏死性凋亡是否参与 GA 诱导的胃癌增殖抑制尚不清楚。在本研究中，我们发现 RIPK1 特异性抑制剂 necrostatin-1 (Nec-1) 减弱 GA 诱导的增殖抑制。GA 处理增加了坏死性凋亡相关蛋白 RIPK1、RIPK3 和 MLKL 的磷酸化，以及它们形成坏死体复合物的相互作用。效应蛋白 Drp-1 通过 GA 处理去磷酸化。不同抑制剂对坏死性凋亡的抑制和 PGAM5 敲低可减弱 GA 诱导的胃癌细胞系细胞死亡，从而减弱 GA 引起的细胞增殖抑制。所有数据都支持GA可以通过诱导坏死性凋亡抑制胃癌细胞增殖的结论。