Peptide-guided targeting of GPR55 and LPAR1 for new therapeutic strategies of cancer
| Autor: | Enrico Iaccino, Maria Giovanna Mosca, Roberta Crescenzo, Calise Serena, Maria Teresa Rizzo, Chiara Polimeni, Selena Mimmi, Cristina Falcone, Camillo Palmieri, Daniela Corda, Ileana Quinto, Giuseppe Scala, Stefania Mariggiò. |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: | |
| Zdroj: | 55° Congresso Nazionale SIC 2013, Catanzaro, 23-26 settembre 2013 info:cnr-pdr/source/autori:Enrico Iaccino, Maria Giovanna Mosca, Roberta Crescenzo, Calise Serena, Maria Teresa Rizzo, Chiara Polimeni, Selena Mimmi, Cristina Falcone, Camillo Palmieri, Daniela Corda, Ileana Quinto, Giuseppe Scala and Stefania Mariggiò./congresso_nome:55° Congresso Nazionale SIC 2013/congresso_luogo:Catanzaro/congresso_data:23-26 settembre 2013/anno:2013/pagina_da:/pagina_a:/intervallo_pagine |
| Popis: | Increasing evidence indicates that G-protein-coupled receptors (GPCRs) are 'druggable' targets in cancer treatment and prevention. Among the members of the GPCR superfamily, the lysophospholipid receptors, and in particular lysophosphatidic acid receptor 1 (LPAR1) and the lysophosphatidylinositol receptor (GPR55), are interesting candidates, as they have roles in the regulation of cancer progression, and their expression correlates with the invasive potential of metastatic cells. In the case of GPR55, several aspects of its physiology are still under investigation, such as its involvement in bone metastasis formation. We propose to target and modulate LPAR1 and GPR55 signaling with peptidic binders. The potential applications for peptidic binders include in-vivo diagnosis of tumor cells, specific delivery of chemotherapeutic agents to cancer cells, and direct modulation of receptor activities with the consequent therapeutic applications. LPAR1 and GPR55 peptidic binders have been identified by screening a M13-phage-displayed random library. To this end, whole-cell-based screening was performed using as bait the full-length LPAR1 and GPR55 receptors heterologously expressed in HEK293 cells. This phage-displayed peptide library consists of combinatorial 7-mers fused to the M13 gene-3 major coat protein. The insert peptides from this library are flanked by a pair of cysteine residues resulting in phage display of cyclized peptides. The diversity of this peptide library is around 109. This method has been used largely in reverse pharmacology to identify ligands for orphan receptors, which represents the 'proof of principle' for the success of this analysis. The ability of the isolated peptides to modulate GPCR function will be evaluated, through the monitoring of their effects on different steps of receptor signaling. Several model systems have been optimized using cells that overexpress these receptors, or that endogenously express them, to study the peptide effects on LPAR1 and GPR55 signaling, tumor cell proliferation, and modulation of actin cytoskeleton organization. Finally, the screening will be extended to primary tumor cells from patients to check whether these peptidic binders could interfere with tumor growth through lysophospholipid receptor targeting. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|