Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424, Taiwan; Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.
Division of Pharmacology and Traditional Chinese Medicine, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University Kaohsiung 80708, Taiwan.
Phytomedicine. 2024 Sep;132:155855. doi: 10.1016/j.phymed.2024.155855. Epub 2024 Jul 4.
Oral squamous cell carcinoma (OSCC) is a frequently occurring type of head and neck cancer with a high mortality and morbidity rate. Rhopaloic acid A (RA), a terpenoid derived from sponges, has demonstrated a promising anti-tumor activity, but its effectiveness for treating OSCC remains unknown.
The aim of this study was to investigate whether RA inhibits the growth of OSCC.
Cell viability was evaluated using CCK-8 assays in OSCC cells (Ca9-22, HSC-3 and SAS) and in normal cells (HGF-1) treated with RA. DAPI staining, AO staining, JC-1 staining and immunofluorescence were used to determine apoptosis, mitochondrial membrane potential and autophagy in RA-treated OSCC cells. Protein expression levels were determined by western blotting. Furthermore, the anti-tumor effect of RA was confirmed in vivo using a zebrafish oral cancer xenotransplantation model.
OSCC cells had a significantly reduced viability after RA treatment, but normal cells were not affected. Treatment with RA caused chromatin condensation in OSCC cells, which increased their expression of autophagy- and apoptosis-related proteins. Furthermore, RA caused mitochondrial damage and increased autophagosome formation. Mitophagy was also induced by RA through the JNK/BNIP3/Nix/LC3B pathway. The JNK inhibitor SP600125 prevented both RA-mediated cell death and mitophagy of OSCC cells. A zebrafish xenograft model demonstrated that RA inhibits OSCC growth.
In conclusion, RA showed a potent anticancer activity in in vitro and in in vivo oral cancer models by promoting mitochondrial damage-induced apoptosis and mitophagy, which suggests that RA may be useful as a novel and effective treatment for OSCC.
口腔鳞状细胞癌（OSCC）是一种常见的头颈部癌症，死亡率和发病率都很高。来源于海绵的萜烯酸 A（RA）具有有希望的抗肿瘤活性，但它治疗 OSCC 的效果尚不清楚。
本研究旨在探讨 RA 是否抑制 OSCC 的生长。
用 CCK-8 法检测 RA 处理的 OSCC 细胞（Ca9-22、HSC-3 和 SAS）和正常细胞（HGF-1）的细胞活力。用 DAPI 染色、AO 染色、JC-1 染色和免疫荧光法检测 RA 处理的 OSCC 细胞中的细胞凋亡、线粒体膜电位和自噬。用 Western blot 法测定蛋白表达水平。此外，还在斑马鱼口腔癌异种移植模型中证实了 RA 的抗肿瘤作用。
RA 处理后 OSCC 细胞活力显著降低，但正常细胞不受影响。RA 处理导致 OSCC 细胞染色质浓缩，增加自噬和凋亡相关蛋白的表达。此外，RA 还导致线粒体损伤和自噬体形成增加。RA 通过 JNK/BNIP3/Nix/LC3B 途径诱导自噬小体的选择性降解（mitophagy）。JNK 抑制剂 SP600125 可阻止 RA 介导的 OSCC 细胞死亡和自噬小体的形成。斑马鱼异种移植模型表明 RA 抑制 OSCC 生长。
总之，RA 通过促进线粒体损伤诱导的细胞凋亡和自噬小体的选择性降解（mitophagy），在体外和体内口腔癌模型中表现出强大的抗癌活性，这表明 RA 可能是治疗 OSCC 的一种新的有效方法。
