Targeting the EGFR/PCNA signaling suppresses tumor growth of triple-negative breast cancer cells with cell-penetrating PCNA peptides

• Published in: PloS one Vol. 8; no. 4; p. e61362
• Main Authors: Yu, Yung-Luen, Chou, Ruey-Hwang, Liang, Jia-Hong, Chang, Wei-Jung, Su, Kuo-Jung, Tseng, Yen-Ju, Huang, Wei-Chien, Wang, Shao-Chun, Hung, Mien-Chie
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 08.04.2013; Public Library of Science (PLoS)
• Subjects: Amino Acid Motifs; Amino Acid Sequence; Angiogenesis; Animals; Antigens; Apoptosis; Biology; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cancer; Cell cycle; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Cell survival; Cell-Penetrating Peptides - chemistry; Cell-Penetrating Peptides - pharmacology; Cell-Penetrating Peptides - therapeutic use; Deoxyribonucleic acid; DNA; Drug Resistance, Neoplasm - drug effects; Enzyme inhibitors; Epidermal growth factor; Epidermal growth factor receptors; Epidermal growth factors; ErbB Receptors - metabolism; Female; Growth; Humans; Kinases; Medical prognosis; Medicine; Mice; Molecular Sequence Data; Molecular Targeted Therapy; Penetration resistance; Peptides; Phosphorylation; Phosphorylation - drug effects; Proliferating cell nuclear antigen; Proliferating Cell Nuclear Antigen - chemistry; Proliferating Cell Nuclear Antigen - metabolism; Prostate cancer; Protein Kinase Inhibitors - pharmacology; Protein-tyrosine kinase; Rodents; Sensitizing; Signal Transduction - drug effects; Signaling; Surgical implants; Tyrosine; Xenograft Model Antitumor Assays; Taiwan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0061362

Tyrosine 211 (Y211) phosphorylation of proliferation cell nuclear antigen (PCNA) coincides with pronounced cancer cell proliferation and correlates with poor survival of breast cancer patients. In epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-resistant cells, both nuclear EGFR (nEGFR) expression and PCNA Y211 phosphorylation are increased. Moreover, the resistance to EGFR TKI is a major clinical problem in treating EGFR-overexpressing triple-negative breast cancer (TNBC). Thus, effective treatment to combat resistance is urgently needed. Here, we show that treatment of cell-penetrating PCNA peptide (CPPP) inhibits growth and induces apoptosis of human TNBC cells. The Y211F CPPP specifically targets EGFR and competes directly for PCNA tyrosine Y211 phosphorylation and prevents nEGFR from binding PCNA in vivo; it also suppresses tumor growth by sensitizing EGFR TKI resistant cells, which have enhanced nEGFR function and abrogated classical EGFR membrane signaling. Furthermore, we identify an active motif of CPPP, RFLNFF (RF6 CPPP), which is necessary and sufficient to inhibit TKI-resistant TNBC cell growth of orthotopic implanted tumor in mice. Finally, the activity of its synthetic retro-inverted derivative, D-RF6 CPPP, on an equimolar basis, is more potent than RF6 CPPP. Our study reveals a drug candidate with translational potential for the future development of safe and effective therapeutic for EGFR TKI resistance in TNBC.