PTPRJ is a receptor protein tyrosine phosphatase whose expression is strongly reduced in the majority of investigated cancer cell lines and tumor specimens. PTPRJ negatively interferes with key players of the mitogenic signaling, including both transmembrane (i.e., HGFR, PDGFR, RET, and VEGFR2) and soluble (i.e., PLCγ1, LAT, c-Src, PI3K, and ERK) targets. We isolated synthetic peptides from a combinatorial phage display library that bind and activate PTPRJ. Among them, PTPRJ-pep19 and PTPRJ-pep24, assayed on both human cancer and primary endothelial cells (HeLa and HUVECs, respectively), induced MAPK dephosphorylation and increased p27Kip1 protein levels; moreover, PTPRJ peptides reduced proliferation and triggered apoptosis of both cell types. To isolate PTPRJ peptides with improved biological activity, we generated a panel of peptides through the Alanine-Scanning approach performed on the native PTPRJpep19 peptide. Among the PTPRJ second-generation peptides, PTPRJ-pep19.4 effectively inhibited HeLa, MCF7, SKBr3 cancer cell proliferation. Moreover, PTPRJpep19.4 was able to block in vitro tube formation on Matrigel. Interestingly, no effects were observed after PTPRJ-pep19.4 treatment of human normal primary epithelial mammary cells (HMECs). PTPRJ peptides were further characterized by molecular modeling and NMR experiments reporting, for the most active peptide, the possibility of self-aggregation states and highlighting new hints of structure-activity relationship. In conclusion, PTPRJ agonist peptides represent lead compounds of great interest for the development of novel and more effective targeted anticancer drugs that can simultaneously target both cancer cell proliferation and tumor angiogenesis.
PTPRJ agonist peptides effectively inhibit in vitro cancer cell proliferation and tube formation
F. Paduano;F. Ortuso;E. Gaudio;V. Dattilo;R. Iuliano;N. Perrotti;S. Alcaro;E. Novellino;A. Fusco;F. Trapasso
2013-01-01
Abstract
PTPRJ is a receptor protein tyrosine phosphatase whose expression is strongly reduced in the majority of investigated cancer cell lines and tumor specimens. PTPRJ negatively interferes with key players of the mitogenic signaling, including both transmembrane (i.e., HGFR, PDGFR, RET, and VEGFR2) and soluble (i.e., PLCγ1, LAT, c-Src, PI3K, and ERK) targets. We isolated synthetic peptides from a combinatorial phage display library that bind and activate PTPRJ. Among them, PTPRJ-pep19 and PTPRJ-pep24, assayed on both human cancer and primary endothelial cells (HeLa and HUVECs, respectively), induced MAPK dephosphorylation and increased p27Kip1 protein levels; moreover, PTPRJ peptides reduced proliferation and triggered apoptosis of both cell types. To isolate PTPRJ peptides with improved biological activity, we generated a panel of peptides through the Alanine-Scanning approach performed on the native PTPRJpep19 peptide. Among the PTPRJ second-generation peptides, PTPRJ-pep19.4 effectively inhibited HeLa, MCF7, SKBr3 cancer cell proliferation. Moreover, PTPRJpep19.4 was able to block in vitro tube formation on Matrigel. Interestingly, no effects were observed after PTPRJ-pep19.4 treatment of human normal primary epithelial mammary cells (HMECs). PTPRJ peptides were further characterized by molecular modeling and NMR experiments reporting, for the most active peptide, the possibility of self-aggregation states and highlighting new hints of structure-activity relationship. In conclusion, PTPRJ agonist peptides represent lead compounds of great interest for the development of novel and more effective targeted anticancer drugs that can simultaneously target both cancer cell proliferation and tumor angiogenesis.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.