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Int. J. Mol. Sci. 2016, 17(10), 1614; doi:10.3390/ijms17101614

APEH Inhibition Affects Osteosarcoma Cell Viability via Downregulation of the Proteasome

1
Institute of Biostructure and Bioimaging, National Research Council (CNR-IBB), Napoli 80134, Italy
2
Institute of Biosciences and BioResources, National Research Council (CNR-IBBR), Napoli 80131, Italy
*
Authors to whom correspondence should be addressed.
Academic Editor: William Chi-shing Cho
Received: 11 July 2016 / Revised: 8 September 2016 / Accepted: 19 September 2016 / Published: 23 September 2016
(This article belongs to the Collection Advances in Molecular Oncology)
View Full-Text   |   Download PDF [3545 KB, uploaded 23 September 2016]   |  

Abstract

The proteasome is a multienzymatic complex that controls the half-life of the majority of intracellular proteins, including those involved in apoptosis and cell-cycle progression. Recently, proteasome inhibition has been shown to be an effective anticancer strategy, although its downregulation is often accompanied by severe undesired side effects. We previously reported that the inhibition of acylpeptide hydrolase (APEH) by the peptide SsCEI 4 can significantly affect the proteasome activity in A375 melanoma or Caco-2 adenocarcinoma cell lines, thus shedding new light on therapeutic strategies based on downstream regulation of proteasome functions. In this work, we investigated the functional correlation between APEH and proteasome in a panel of cancer cell lines, and evaluated the cell proliferation upon SsCEI 4-treatments. Results revealed that SsCEI 4 triggered a proliferative arrest specifically in osteosarcoma U2OS cells via downregulation of the APEH–proteasome system, with the accumulation of the typical hallmarks of proteasome: NF-κB, p21Waf1, and polyubiquitinylated proteins. We found that the SsCEI 4 anti-proliferative effect involved a senescence-like growth arrest without noticeable cytotoxicity. These findings represent an important step toward understanding the mechanism(s) underlying the APEH-mediated downregulation of proteasome in order to design new molecules able to efficiently regulate the proteasome system for alternative therapeutic strategies. View Full-Text
Keywords: acylpeptide hydrolase (APEH); proteasome; osteosarcoma cell lines; peptide inhibitor; anti-tumoral target acylpeptide hydrolase (APEH); proteasome; osteosarcoma cell lines; peptide inhibitor; anti-tumoral target
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MDPI and ACS Style

Palumbo, R.; Gogliettino, M.; Cocca, E.; Iannitti, R.; Sandomenico, A.; Ruvo, M.; Balestrieri, M.; Rossi, M.; Palmieri, G. APEH Inhibition Affects Osteosarcoma Cell Viability via Downregulation of the Proteasome. Int. J. Mol. Sci. 2016, 17, 1614.

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