Wu Jiaxue, Li Qianqian, Cheng Xiangyu, Dai Chenjie, Huang Qingxing, Wang Yusheng
Shanxi Medical University, Taiyuan, Shanxi, 030001, China.
Department of Oncology Digestive, First Hospital of Shanxi Tumor Hospital, Taiyuan, 030013, Shanxi, China.
Curr Cancer Drug Targets. 2025 Jul 15. doi: 10.2174/0115680096388633250704101500.
RC48 is an anti-HER2 antibody‒drug conjugate that demonstrates antitumor activity in colon cancer with both high and low HER2 expression. Our study aimed to investigate the underlying mechanisms of RC48 on colon cancer cells with varying levels of HER2 expression.
The effects of RC48 on HER2 high-expressing HT29 colon cancer cells and low-expressing SW480 cells were assessed using transwell assays and flow cytometry. Proteomic analysis was carried out to explore the mechanisms by which RC48 inhibits the growth of HT29 and SW480 cells. β-Galactosidase staining and ELISAs were performed to validate the promotion of senescence in colon cancer cells by RC48. Bioinformatics analysis revealed the correlation between differentially expressed proteins and HER2 expression.
RC48 inhibited the growth of HT29 and SW480 cells. Proteomic analysis revealed that RC48 enhanced CDKN1A expression in HT29 and SW480 cells. KEGG analysis indicated that CDKN1A expression was associated with the cellular senescence signaling pathway. RC48 upregulated CDKN1A expression in HT29 and SW480 cells, whereas the expression of other proteins related to the cellular senescence pathway was reduced. CDKN1A gene overexpression suppressed HT29 and SW480 cells. β-Gal staining demonstrated that RC48 promoted senescence in colon cancer cells, and RC48 enhanced senescence-associated secretory phenotype factor secretion in ELISAs. The close correlation between CDKN1A and HER2 expression was derived from the database.
This study provides important insights into the antitumor mechanism of RC48, suggesting for the first time that CDKN1A-mediated cellular senescence may be a key mechanism underlying its therapeutic effect in HER2-high and low-expressing colon cancer, thereby offering a new theoretical basis for optimizing its clinical application. However, in vivo and clinical validation are lacking, and the functional role of CDKN1A, as well as its regulatory relationship with HER2, requires further investigation.
RC48 exerts antitumor effects on both HER2-high- and HER2-low-expressing colon cancer cells. RC48 may induce senescence in both high- and low-HER2 expressing co-lon cancer cells by increasing CDKN1A protein expression. Moreover, there is a close correlation between CDKN1A and HER2 expression.
RC48是一种抗HER2抗体药物偶联物，在HER2高表达和低表达的结肠癌中均显示出抗肿瘤活性。我们的研究旨在探讨RC48对不同HER2表达水平的结肠癌细胞的潜在作用机制。
使用Transwell实验和流式细胞术评估RC48对HER2高表达的HT29结肠癌细胞和低表达的SW480细胞的影响。进行蛋白质组学分析以探索RC48抑制HT29和SW480细胞生长的机制。进行β-半乳糖苷酶染色和酶联免疫吸附测定以验证RC48对结肠癌细胞衰老的促进作用。生物信息学分析揭示了差异表达蛋白与HER2表达之间的相关性。
RC48抑制了HT29和SW480细胞的生长。蛋白质组学分析显示，RC48增强了HT29和SW480细胞中CDKN1A的表达。KEGG分析表明，CDKN1A的表达与细胞衰老信号通路相关。RC48上调了HT29和SW480细胞中CDKN1A的表达，而与细胞衰老途径相关的其他蛋白质的表达则降低。CDKN1A基因过表达抑制了HT29和SW480细胞。β-半乳糖苷酶染色表明，RC48促进了结肠癌细胞的衰老，并且在酶联免疫吸附测定中RC48增强了衰老相关分泌表型因子的分泌。从数据库中得出CDKN1A与HER2表达之间存在密切相关性。
本研究为RC48的抗肿瘤机制提供了重要见解，首次表明CDKN1A介导的细胞衰老可能是其在HER2高表达和低表达结肠癌中发挥治疗作用背后的关键机制，从而为优化其临床应用提供了新的理论依据。然而，缺乏体内和临床验证，CDKN1A的功能作用及其与HER2的调控关系需要进一步研究。
RC48对HER2高表达和HER2低表达的结肠癌细胞均具有抗肿瘤作用。RC48可能通过增加CDKN1A蛋白表达在HER2高表达和低表达的结肠癌细胞中诱导衰老。此外，CDKN1A与HER2表达之间存在密切相关性。
