Gogliettino, Marta (2014) Proteasome and Acylpeptide hydrolase system: exploring an alternative strategy in cancer therapy. [Tesi di dottorato]
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| Item Type: | Tesi di dottorato |
|---|---|
| Resource language: | English |
| Title: | Proteasome and Acylpeptide hydrolase system: exploring an alternative strategy in cancer therapy |
| Creators: | Creators Email Gogliettino, Marta marta.gogliettino@libero.it |
| Date: | 29 March 2014 |
| Number of Pages: | 159 |
| Institution: | Università degli Studi di Napoli Federico II |
| Department: | Biologia |
| Scuola di dottorato: | Scienze biologiche |
| Dottorato: | Biologia applicata |
| Ciclo di dottorato: | 26 |
| Coordinatore del Corso di dottorato: | nome email Ricca, Ezio ericca@unina.it |
| Tutor: | nome email Palmieri, Gianna UNSPECIFIED |
| Date: | 29 March 2014 |
| Number of Pages: | 159 |
| Keywords: | APEH,proteasome, cancer cells, protease inhibitors |
| Settori scientifico-disciplinari del MIUR: | Area 05 - Scienze biologiche > BIO/10 - Biochimica |
| Date Deposited: | 07 Apr 2014 15:38 |
| Last Modified: | 27 Jan 2015 13:59 |
| URI: | http://www.fedoa.unina.it/id/eprint/9769 |
Collection description
Acylpeptide hydrolase (APEH), one of the four members of the prolyl oligopeptidase class, catalyses the removal of Nacylated amino acids from acetylated peptides and it has been postulated to play a key role in protein degradation machinery. Disruption of protein turnover has been established as an effective strategy to down-regulate the ubiquitinproteasome system (UPS) and as a promising approach in anticancer therapy. Here, we illustrate a new pathway modulating UPS and proteasome activity through inhibition of APEH. To find novel molecules able to down-regulate APEH activity, we screened a set of synthetic peptides, reproducing the reactive-site loop of a known archaeal inhibitor of APEH (SsCEI), and the conjugated linoleic acid (CLA) isomers. A 12-mer SsCEI peptide and the trans10-cis12 isomer of CLA, were identified as specific APEH inhibitors and their effects on cell-based assays were paralleled by a dose-dependent reduction of proteasome activity. Moreover, cell treatment with the individual compounds increased the cytoplasm levels of several classic hallmarks of proteasome inhibition, such as NFkappaB and misfolded or polyubiquitinylated proteins, without any cytotoxicity. Remarkably, transfection of human bronchial epithelial cells with APEH siRNA, promoted a marked accumulation of a mutant of the cystic fibrosis transmembrane conductance regulator (CFTR), herein used as a model of misfolded protein typically degraded by UPS. Our study supports a previously unrecognized role of APEH as a negative effector of proteasome activity by an unknown mechanism and opens new perspectives for the development of strategies aimed at modulation of cancer progression.
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