APEH Inhibition Affects Osteosarcoma Cell Viability via Downregulation of the Proteasome

• Main Authors: Rosanna Palumbo, Marta Gogliettino, Ennio Cocca, Roberta Iannitti, Annamaria Sandomenico, Menotti Ruvo, Marco Balestrieri, Mosè Rossi, Gianna Palmieri
• Format: Article
• Language: English
• Published: MDPI AG 2016-09-01
• Series: International Journal of Molecular Sciences
• Subjects: acylpeptide hydrolase (APEH); proteasome; osteosarcoma cell lines; peptide inhibitor; anti-tumoral target
• Online Access: http://www.mdpi.com/1422-0067/17/10/1614

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.