APEH Inhibition Affects Osteosarcoma Cell Viability via Downregulation of the Proteasome

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 of...

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Published inInternational journal of molecular sciences Vol. 17; no. 10; p. 1614
Main Authors Palumbo, Rosanna, Gogliettino, Marta, Cocca, Ennio, Iannitti, Roberta, Sandomenico, Annamaria, Ruvo, Menotti, Balestrieri, Marco, Rossi, Mosè, Palmieri, Gianna
Format Journal Article
LanguageEnglish
Published Switzerland MDPI AG 01.10.2016
MDPI
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Summary: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, p21(Waf1), 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.
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These authors contributed equally to this work.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms17101614