Identification, characterization and application of a new peptide against anterior gradient homolog 2 (AGR2).

Autor: Garri C; Keck School of Medicine, Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA, USA., Howell S; Department of Chemistry, University of Southern California, Los Angeles, CA, USA., Tiemann K; Keck School of Medicine, Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA, USA., Tiffany A; Mork Family Department of Chemical Engineering and Material Science, University of Southern California, Los Angeles, CA, USA., Jalali-Yazdi F; Mork Family Department of Chemical Engineering and Material Science, University of Southern California, Los Angeles, CA, USA., Alba MM; Keck School of Medicine, Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA, USA., Katz JE; Keck School of Medicine, Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA, USA., Takahashi TT; Department of Chemistry, University of Southern California, Los Angeles, CA, USA., Landgraf R; University of Miami, Miller School of Medicine, Department of Biochemistry and Molecular Biology, Miami, FL, USA., Gross ME; Keck School of Medicine, Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA, USA.; USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA., Roberts RW; USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA.; Department of Chemistry, University of Southern California, Los Angeles, CA, USA.; Mork Family Department of Chemical Engineering and Material Science, University of Southern California, Los Angeles, CA, USA., Kani K; Keck School of Medicine, Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA, USA.; USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
Jazyk: angličtina
Zdroj: Oncotarget [Oncotarget] 2018 Jun 08; Vol. 9 (44), pp. 27363-27379. Date of Electronic Publication: 2018 Jun 08 (Print Publication: 2018).
DOI: 10.18632/oncotarget.25221
Abstrakt: The cancer-associated protein Anterior Gradient 2 (AGR2) has been described, predominantly in adenocarcinomas. Increased levels of extracellular AGR2 (eAGR2) have been correlated with poor prognosis in cancer patients, making it a potential biomarker. Additionally, neutralizing AGR2 antibodies showed preclinical effectiveness in murine cancer models suggesting eAGR2 may be a therapeutic target. We set out to identify a peptide by mRNA display that would serve as a theranostic tool targeting AGR2. This method enables the selection of peptides from a complex (>10 11 ) library and incorporates a protease incubation step that filters the selection for serum stable peptides. We performed six successive rounds of enrichment using a 10-amino acid mRNA display library and identified several AGR2 binding peptides. One of these peptides (H10), demonstrated high affinity binding to AGR2 with a binding constant (K D ) of 6.4 nM. We developed an AGR2 ELISA with the H10 peptide as the capture reagent. Our H10-based ELISA detected eAGR2 from cancer cell spent media with a detection limit of (20-50 ng/ml). Furthermore, we investigated the therapeutic utility of H10 and discovered that it inhibited cell viability at IC 50 (9-12 μmoles/L) in cancer cell lines. We also determined that 10 μg/ml of H10 was sufficient to inhibit cancer cell migration in breast and prostate cancer cell lines. A control peptide did not show any appreciable activity in these cells. The H10 peptide showed promise as both a novel diagnostic and a potential therapeutic peptide.
Competing Interests: CONFLICTS OF INTEREST No potential conflicts of interest was reported by the authors.
Databáze: MEDLINE
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