Dual inhibition of ErbB1 and ErbB2 in cancer by recombinant human prolidase mutant hPEPD-G278D.

Abstract

ErbB1 and ErbB2 are oncogenic cell surface receptor tyrosine kinases, linked to many forms of human cancer, and are major cancer therapeutic targets. Many lines of evidence indicate that targeting ErbB1 and ErbB2 is an important cancer therapeutic approach. We recently found that a recombinant enzymatically-inactive mutant of human prolidase, i.e., hPEPD-G278D, is an inhibitory ligand of ErbB2 and strongly inhibits ErbB2-overexpressing cells in vitro and in vivo. hPEPD-G278D also binds to ErbB1. Here, we show that hPEPD-G278D binds to ErbB1 with high affinity, initially activating ErbB1 but later silencing it, and that deletion of subdomain 2 in ErbB1 extracellular domain abolishes the binding. The proliferation of ErbB1-overexpressing cells is strongly inhibited by hPEPD-G278D, regardless of ErbB2 expression or cell type, whereas cells lacking ErbB1 and ErbB2 are insensitive to it. In contrast, EGF, another ErbB1 ligand, either stimulates or mildly inhibits cell proliferation. Moreover, hPEPD-G278D treatment of mice bearing ErbB1-overexpressing tumors leads to tumor regression, which is accompanied by down regulation and decreased phosphorylation of ErbB1 and ErbB2 as well as decreased phosphorylation of downstream signaling molecules and activation of apoptosis in the tumor tissues. We conclude that hPEPD-G278D is a dual inhibitor of ErbB1 and ErbB2 and selectively targets cancer cells overexpressing ErbB1 and/or ErbB2. Moreover, our finding that both receptors are silenced in cancer cells by hPEPD-G278D highlights an unusual consequence of ligand-receptor interaction.

• Authors: Lu Yang, Yun Li, Arup Bhattacharya, Yuesheng Zhang
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 27 Pg. 42340-42352 (Jul 05 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27286447 (Publication Type: Journal Article)

Chemical References

• Ligands
• Mutant Proteins
• Recombinant Proteins
• EGFR protein, human
• ERBB2 protein, human
• ErbB Receptors
• Receptor, ErbB-2
• Dipeptidases
• proline dipeptidase

Topics

• Animals
• Apoptosis (drug effects)
• Cell Proliferation
• Dipeptidases (metabolism)
• ErbB Receptors (antagonists & inhibitors)
• Gene Expression Regulation, Neoplastic
• Gene Silencing
• Humans
• Ligands
• Mice
• Mutant Proteins (metabolism)
• Neoplasms (metabolism)
• Phosphorylation
• Protein Binding
• Receptor, ErbB-2 (antagonists & inhibitors)
• Recombinant Proteins (metabolism)
• Remission Induction
• Signal Transduction (drug effects)