Scholarlink

Background <p>Chemoresistance is a cause of chemotherapy failure in gastric cancer (GC) treatment. Recent studies have shown that the dysregulation of glutamine metabolism plays a pivotal role in promoting chemoresistance. While small-molecule inhibitors targeting glutamine metabolism have been investigated, peptide-based compounds have attracted increasing attention because of their high specificity and low toxicity. Endogenous or rationally designed peptides have shown potential for inducing apoptosis, disrupting cancer-related signaling pathways, and overcoming drug resistance in various cancers. However, the potential of functional peptides to target glutamine metabolism and reverse drug resistance in the context of GC has not been thoroughly explored.</p> Methods <p>We performed proteomic profiling to identify upregulated proteins in cisplatin-sensitive GC cells, from which peptides were derived for functional screening. A RHOJ-derived peptide (peptide 1) was identified and validated as a candidate chemosensitizer. Untargeted metabolomics, flow cytometry, molecular docking, molecular dynamics simulations, fluorescence imaging, and a subcutaneous xenograft model were used to investigate the mechanism through which peptide 1 modulates GLUL-mediated glutamine metabolism and reverses cisplatin resistance.</p> Results <p>In this study, we found that glutamine metabolism was enhanced in cisplatin-resistant GC cells and that a peptide which derived from RHOJ (peptide 1) increased the sensitivity of resistant cells to chemotherapy. Molecular docking revealed that this peptide could bind to glutamine synthetase (GLUL), a key enzyme in the glutamine metabolism pathway. Mechanistically, peptide 1 inhibited glutamine production, increased ROS levels, induced DNA damage, and promoted apoptosis in resistant cells, ultimately restoring cisplatin sensitivity both in vitro and in vivo.</p> Conclusions <p>Our study demonstrated that glutamine metabolism plays a vital role in the chemoresistance of GC cells and that RHOJ-derived peptide 1 enhances the chemosensitivity of drug-resistant GC cells through targeting GLUL, depleting glutamine, inducing ROS accumulation, and promoting DNA damage. These mechanisms ultimately restores chemosensitivity in drug-resistant cells and highlight peptide 1 as a promising therapeutic strategy for overcoming chemoresistance in GC.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

RHOJ derived peptide promotes chemosensitivity by inhibiting glutamine metabolism in gastric cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月28日

查看全文
  • Jian Li,
  • Huanqing Li,
  • Fangzhou Ye,
  • Jiayi Wang,
  • Fan Li,
  • Songhua Bei,
  • Xiaohong Zhang,
  • Jun Jiang,
  • Li Feng

摘要

Background

Chemoresistance is a cause of chemotherapy failure in gastric cancer (GC) treatment. Recent studies have shown that the dysregulation of glutamine metabolism plays a pivotal role in promoting chemoresistance. While small-molecule inhibitors targeting glutamine metabolism have been investigated, peptide-based compounds have attracted increasing attention because of their high specificity and low toxicity. Endogenous or rationally designed peptides have shown potential for inducing apoptosis, disrupting cancer-related signaling pathways, and overcoming drug resistance in various cancers. However, the potential of functional peptides to target glutamine metabolism and reverse drug resistance in the context of GC has not been thoroughly explored.

Methods

We performed proteomic profiling to identify upregulated proteins in cisplatin-sensitive GC cells, from which peptides were derived for functional screening. A RHOJ-derived peptide (peptide 1) was identified and validated as a candidate chemosensitizer. Untargeted metabolomics, flow cytometry, molecular docking, molecular dynamics simulations, fluorescence imaging, and a subcutaneous xenograft model were used to investigate the mechanism through which peptide 1 modulates GLUL-mediated glutamine metabolism and reverses cisplatin resistance.

Results

In this study, we found that glutamine metabolism was enhanced in cisplatin-resistant GC cells and that a peptide which derived from RHOJ (peptide 1) increased the sensitivity of resistant cells to chemotherapy. Molecular docking revealed that this peptide could bind to glutamine synthetase (GLUL), a key enzyme in the glutamine metabolism pathway. Mechanistically, peptide 1 inhibited glutamine production, increased ROS levels, induced DNA damage, and promoted apoptosis in resistant cells, ultimately restoring cisplatin sensitivity both in vitro and in vivo.

Conclusions

Our study demonstrated that glutamine metabolism plays a vital role in the chemoresistance of GC cells and that RHOJ-derived peptide 1 enhances the chemosensitivity of drug-resistant GC cells through targeting GLUL, depleting glutamine, inducing ROS accumulation, and promoting DNA damage. These mechanisms ultimately restores chemosensitivity in drug-resistant cells and highlight peptide 1 as a promising therapeutic strategy for overcoming chemoresistance in GC.