2. Academic Validation
  3. A specific RAGE-binding peptide inhibits triple negative breast cancer growth through blocking of Erk1/2/NF-κB pathway

A specific RAGE-binding peptide inhibits triple negative breast cancer growth through blocking of Erk1/2/NF-κB pathway

  • Eur J Pharmacol. 2023 Jun 26;954:175861. doi: 10.1016/j.ejphar.2023.175861.
Xiaoyong Dai 1,  Yibo Hou 1,  Ting Deng 1,  Gaoyang Lin 1,  Yuanxiong Cao 1,  Guiyuan Yu 2,  Wei Wei 3,  Qing Zheng 4,  Laiqiang Huang 5,  Shaohua Ma 6
Affiliations

Affiliations

  • 1 Institute of Biopharmaceutical and Health Engineering, Shenzhen Key Laboratory of Gene and Antibody Therapy, State Key Laboratory of Chemical Oncogenomics, Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong, 518055, China.
  • 2 Shenzhen Maternal and Child Health Hospital Affiliated to Southern Medical University, Shenzhen, Guangdong, China.
  • 3 The Department of Breast and Thyroid Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong, 518036, China.
  • 4 College of Pharmacy, Jinan University, 510632 Guangzhou, Guangdong, People's Republic of China.
  • 5 Institute of Biopharmaceutical and Health Engineering, Shenzhen Key Laboratory of Gene and Antibody Therapy, State Key Laboratory of Chemical Oncogenomics, Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong, 518055, China. Electronic address: huanglq@tsinghua.edu.cn.
  • 6 Institute of Biopharmaceutical and Health Engineering, Shenzhen Key Laboratory of Gene and Antibody Therapy, State Key Laboratory of Chemical Oncogenomics, Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong, 518055, China. Electronic address: ma.shaohua@sz.tsinghua.edu.cn.
PMID: 37380046 DOI: 10.1016/j.ejphar.2023.175861
Abstract

Triple-negative breast Cancer (TNBC) is an aggressive Cancer that poses a significant threat to women's health. Unfortunately, the lack of clinical targets leads the poor clinical outcomes in TNBC. Many cancers demonstrate overexpression of receptor for advanced glycation end products (RAGE), which can contribute to Cancer progression. Despite the potential therapeutic value of blocking RAGE for TNBC treatment, effective peptide drugs have yet to be developed. In our study, we observed that RAGE was highly expressed in TNBC and was associated with poor disease progression. We subsequently investigated the antitumor effects and underlying mechanisms of the RAGE antagonist peptide RP7 in both in vitro and in vivo models of TNBC. Our study revealed that RP7 selectively binds to RAGE-overexpressing TNBC cell lines, including MDA-MB-231 and BT549, and significantly inhibits cell viability, migration, and invasion in both cell lines. Furthermore, RP7-treatment suppressed tumor growth in TNBC xenograft mouse models without inducing detectable toxicity in normal tissues. Mechanistically, RP7 was found to inhibit the phosphorylation of ERK1/2, IKKα/β, IKBα, and p65 to block the NF-κB pathway, prevent the entry of p65 into the nucleus, decrease the protein expression of Bcl-2 and HMGB1, and promote the release of cytochrome C from the mitochondria into the cytoplasm. These effects were observed to activate Apoptosis and inhibit epithelial-mesenchymal transition (EMT) in TNBC cells. This study highlights RAGE as a candidate therapeutic target for TNBC treatment and suggests that the RAGE antagonist peptide RP7 is a promising Anticancer drug for TNBC.

Keywords

Apoptosis; HMGB1; NF-κB pathway; RAGE; RP7; TNBC.

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