Ji Shuting, Aswathy Maniyamma, Kuboki Yuya, Takada Yoshio, Toshima Kazunobu, Takahashi Daisuke, Ideo Hiroko
Laboratory of Glycobiology, The Noguchi Institute, 1-9-7, Kaga, Itabashi, Tokyo 173-0003, Japan.
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1, Hiyoshi, Kouhoku-ku, Yokohama 223-8522, Kanagawa, Japan.
Int J Mol Sci. 2025 Sep 21;26(18):9228. doi: 10.3390/ijms26189228.
In malignant-type gastric cancer, peritoneal dissemination is the most frequent metastatic process and is an inoperable condition for which effective treatment is lacking. Our research has revealed that galectin-4 plays an important role in the peritoneal metastasis of gastric cancer cells. Based on this, we hypothesized that inhibiting galectin-4 could suppress peritoneal metastasis. The inhibitory activity towards galectin-4 binding was evaluated using an enzyme-linked immunosorbent assay, while the suppressive effect on gastric cancer cell proliferation was assessed using an adenosine triphosphate-based cell viability assay. Direct binding to galectin-4 was examined by surface plasmon resonance analysis. Chemically synthesized fucoidan analogs exhibited significant suppressive activity against the proliferation of gastric cancer cells, partly via a galectin-4-mediated pathway. Among the 13 fucoidan analogs tested, analog , whose sugar chains composed of repeating 2,3--sulfated α(1,4)-linked L-fucose, showed significant inhibitory activity against galectin-4 binding and cell proliferation. , the cholestanol-conjugated analog , exhibited a pronounced increase in inhibitory activity, consistent with potential multimerization. Molecular docking and site-directed mutagenesis studies revealed that Arginine-45 in galectin-4 is important for binding to fucoidan analogs. In conclusion, fucoidan analogs with a strong affinity for galectin-4 are promising candidates for inhibiting the peritoneal metastasis of galectin-4-positive gastric cancer cells.
在恶性型胃癌中，腹膜播散是最常见的转移过程，且是一种缺乏有效治疗方法的不可手术的病症。我们的研究表明，半乳糖凝集素-4在胃癌细胞的腹膜转移中起重要作用。基于此，我们推测抑制半乳糖凝集素-4可抑制腹膜转移。使用酶联免疫吸附测定法评估对半乳糖凝集素-4结合的抑制活性，同时使用基于三磷酸腺苷的细胞活力测定法评估对胃癌细胞增殖的抑制作用。通过表面等离子体共振分析检测与半乳糖凝集素-4的直接结合。化学合成的岩藻依聚糖类似物对胃癌细胞的增殖表现出显著的抑制活性，部分是通过半乳糖凝集素-4介导的途径。在所测试的13种岩藻依聚糖类似物中，其糖链由重复的2,3-硫酸化α(1,4)-连接的L-岩藻糖组成的类似物，对半乳糖凝集素-4结合和细胞增殖表现出显著的抑制活性。胆甾醇共轭类似物表现出抑制活性的显著增加，这与潜在的多聚化一致。分子对接和定点诱变研究表明，半乳糖凝集素-4中的精氨酸-45对于与岩藻依聚糖类似物的结合很重要。总之，对半乳糖凝集素-4具有强亲和力的岩藻依聚糖类似物是抑制半乳糖凝集素-4阳性胃癌细胞腹膜转移的有前途的候选物。
