title: Inhibition of ERBB2-overexpressing Tumors by Recombinant Human Prolidase and Its Enzymatically Inactive Mutant.
abstract: ERBB2 is an oncogenic receptor tyrosine kinase overexpressed in a subset of human breast cancer and other cancers. We recently found that human prolidase (PEPD), a dipeptidase, is a high affinity ERBB2 ligand and cross-links two ERBB2 monomers. Here, we show that recombinant human PEPD (rhPEPD) strongly inhibits ERBB2-overexpressing tumors in mice, whereas it does not impact tumors without ERBB2 overexpression. rhPEPD causes ERBB2 depletion, disrupts oncogenic signaling orchestrated by ERBB2 homodimers and heterodimers, and induces apoptosis. The impact of enzymatically-inactive mutant rhPEPDG278Don ERBB2 is indistinguishable from that of rhPEPD, but rhPEPDG278Dis superior to rhPEPD for tumor inhibition. The enzymatic function of rhPEPD stimulates HIF-1α and other pro-survival factors in tumors, which likely attenuates its antitumor activity. rhPEPDG278Dis also attractive in that it may not interfere with the physiologic function of endogenous PEPD in normal cells. Collectively, we have identified a human protein as an inhibitory ERBB2 ligand that inhibits ERBB2-overexpressing tumorsin vivo. Several anti-ERBB2 agents are on the market but are hampered by drug resistance and high drug cost. rhPEPDG278Dmay synergize with these agents and may also be highly cost-effective, since it targets ERBB2 with a different mechanism and can be produced in bacteria.
authors.affiliation: Department of Chemoprevention, Roswell Park Cancer Institute, Buffalo, NY 14263, United States.
authors.forename: Lu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Chemoprevention, Roswell Park Cancer Institute, Buffalo, NY 14263, United States ; Department of Urology, Roswell Park Cancer Institute, Buffalo, NY 14263, Unites States.
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Chemoprevention, Roswell Park Cancer Institute, Buffalo, NY 14263, United States.
authors.forename: Arup
authors.initials: A
authors.lastname: Bhattacharya
authors.affiliation: Department of Chemoprevention, Roswell Park Cancer Institute, Buffalo, NY 14263, United States.
authors.forename: Yuesheng
authors.initials: Y
authors.lastname: Zhang
keywords: ERBB2; ERBB2 ligand; PEPD; anti-ERBB2 agent; prolidase