CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Gambogic acid induces GSDME dependent pyroptotic signaling pathway via ROS/P53/Mitochondria/Caspase-3 in ovarian cancer cells.
Gambogic acid induces GSDME dependent pyroptotic signaling pathway via ROS/P53/Mitochondria/Caspase-3 in ovarian cancer cells.
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藤黄酸（GA）是一种从藤黄中提取的天然活性化合物，具有多种抗癌活性。然而，GA是否诱导卵巢癌（OC）发生细胞焦亡（一种新发现的炎症介导的程序性细胞死亡机制）尚未见报道。
本研究揭示，GA处理通过诱导OC细胞系发生细胞焦亡而降低细胞活力。观察到典型的细胞焦亡形态学表现，如细胞肿胀伴大泡形成及细胞膜完整性丧失。GA处理后cleaved caspase-3和GSDME-N水平升高，敲除GSDME或使用caspase-3抑制剂可将GA诱导的细胞死亡从细胞焦亡转变为细胞凋亡，表明GA诱导caspase-3/GSDME依赖性细胞焦亡。
此外，本研究表明GA显著增加活性氧（ROS）和p53磷酸化。用ROS抑制剂N-乙酰半胱氨酸（NAC）和特异性p53抑制剂pifithrin-μ预处理的OC细胞可完全逆转处理后的细胞焦亡。p53及磷酸化p53升高降低线粒体膜电位（MMP）和Bcl-2，增加Bax表达，并通过释放细胞色素c损伤线粒体以激活下游细胞焦亡通路。不同剂量的GA抑制ID8荷瘤小鼠的肿瘤生长，高剂量GA组肿瘤组织中检测到TIL（肿瘤浸润淋巴细胞）CD3、CD4和CD8增加。
值得注意的是，高剂量GA组肿瘤组织中GSDME-N、cleaved caspase-3及其他蛋白表达增加。这些发现表明，GA处理的OC细胞可通过ROS/p53/线粒体信号通路及caspase-3/-9激活诱导GSDME介导的细胞焦亡。因此，GA是OC治疗中一种有前景的治疗药物。
Gambogic acid (GA) is a naturally active compound extracted from the Garcinia hanburyi with various anticancer activities.
However, whether GA induces pyroptosis (a newly discovered inflammation-mediated programmed cell death mechanism) in ovarian cancer (OC) has not yet been reported.
This study revealed that GA treatment reduced cell viability by inducing pyroptosis in OC cell lines. Typical pyroptosis morphological manifestations such as cell swelling with large bubbles and loss of cell membrane integrity, were observed. Cleaved caspase-3 and GSDME-N levels increased after GA treatment, and knocking out GSDME or using a caspase-3 inhibitor could switch GA-induced cell death from pyroptosis to apoptosis, indicating GA induced caspase-3/GSDME-dependent pyroptosis.
Furthermore, this research indicated that GA significantly increased reactive oxygen species (ROS) and p53 phosphorylation. OC cells pretreated with ROS inhibitor N-Acetylcysteine (NAC) and the specific p53 inhibitor pifithrin-μ could completely reverse the pyroptosis post-treatment.
Elevated p53 and phosphorylated p53 reduced mitochondrial membrane potential (MMP) and Bcl-2, increase the expression of Bax, and damage mitochondria by releasing cytochrome c to activate the downstream pyroptosis pathway. Different doses of GA inhibited tumor growth in ID8 tumor-bearing mice, and high-dose GA increased in tumor-infiltrating lymphocytes CD3, CD4, and CD8 were detected in tumor tissues.
Notably, the expressions of GSDME-N, cleaved caspase-3 and other proteins were increased in tumor tissues with high-dose GA groups.
These findings demonstrate that GA-treated OC cells could induce GSDME-mediated pyroptosis through the ROS/p53/mitochondria signaling pathway and caspase-3/-9 activation.
Thus, GA is a promising therapeutic agent for OC treatment.
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