2-溴棕桐酸通过阻碍 Ras 蛋白的膜定位来抑制 HPSCC 细胞的恶性行为。
2-Bromopalmitate inhibits malignant behaviors of HPSCC cells by hindering the membrane location of Ras protein.
机构信息
Department of Otorhinolaryngology Head and Neck Surgery, Shandong Provincial Hospital, Shandong University, Jinan 250021, China.
Shandong Provincial Hospital, Shandong University, Jinan 250021, China.
出版信息
Exp Biol Med (Maywood). 2023 Dec;248(23):2393-2407. doi: 10.1177/15353702231220671. Epub 2023 Dec 30.
Palmitoylation, which is mediated by protein acyltransferase (PAT) and performs important biological functions, is the only reversible lipid modification in organism. To study the effect of protein palmitoylation on hypopharyngeal squamous cell carcinoma (HPSCC), the expression levels of 23 PATs in tumor tissues of 8 HPSCC patients were determined, and high mRNA and protein levels of DHHC9 and DHHC15 were found. Subsequently, we investigated the effect of 2-bromopalmitate (2BP), a small-molecular inhibitor of protein palmitoylation, on the behavior of Fadu cells in vitro (50 μM) and in nude mouse xenograft models (50 μmol/kg), and found that 2BP suppressed the proliferation, invasion, and migration of Fadu cells without increasing cell apoptosis. Mechanistically, the effect of 2BP on the transduction of BMP, Wnt, Shh, and FGF signaling pathways was tested with qRT-PCR, and its drug target was explored with western blotting and acyl-biotinyl exchange assay. Our results showed that 2BP inhibited the transduction of the FGF/ERK signaling pathway. The palmitoylation level of Ras protein decreased after 2BP treatment, and its distribution in the cell membrane structure was reduced significantly. The findings of this work reveal that protein palmitoylation mediated by DHHC9 and DHHC15 may play important roles in the occurrence and development of HPSCC. 2BP is able to inhibit the malignant biological behaviors of HPSCC cells, possibly via hindering the palmitoylation and membrane location of Ras protein, which might, in turn, offer a low-toxicity anti-cancer drug for targeting the treatment of HPSCC.
棕榈酰化作用由蛋白酰基转移酶（PAT）介导，具有重要的生物学功能，是生物体内唯一的可逆脂质修饰。为了研究蛋白棕榈酰化对下咽鳞癌（HPSCC）的影响，检测了 8 例 HPSCC 患者肿瘤组织中 23 种 PAT 的表达水平，发现 DHHC9 和 DHHC15 的 mRNA 和蛋白水平较高。随后，我们研究了小分子蛋白棕榈酰化抑制剂 2-溴棕榈酸（2BP）在体外（50μM）和裸鼠异种移植模型（50μmol/kg）中对 Fadu 细胞行为的影响，发现 2BP 抑制 Fadu 细胞的增殖、侵袭和迁移，而不增加细胞凋亡。在机制上，我们用 qRT-PCR 测试了 2BP 对 BMP、Wnt、Shh 和 FGF 信号通路转导的影响，用 Western blot 和酰基辅酶 A 交换测定法探索了其药物靶点。结果表明，2BP 抑制了 FGF/ERK 信号通路的转导。2BP 处理后 Ras 蛋白的棕榈酰化水平降低，其在细胞膜结构中的分布显著减少。这项工作的结果表明，DHHC9 和 DHHC15 介导的蛋白棕榈酰化可能在下咽鳞癌的发生和发展中发挥重要作用。2BP 能够抑制 HPSCC 细胞的恶性生物学行为，可能是通过抑制 Ras 蛋白的棕榈酰化和膜定位，从而为靶向治疗 HPSCC 提供一种低毒性的抗癌药物。
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