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 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.
Institute of Biostructure and Bioimaging, National Research Council (CNR-IBB), Napoli 80134, Italy. rosanna.palumbo@cnr.it.
Rosanna
R
Palumbo
Institute of Biosciences and BioResources, National Research Council (CNR-IBBR), Napoli 80131, Italy. marta.gogliettino@ibbr.cnr.it.
Marta
M
Gogliettino
Institute of Biosciences and BioResources, National Research Council (CNR-IBBR), Napoli 80131, Italy. ennio.cocca@ibbr.cnr.it.
Ennio
E
Cocca
Institute of Biostructure and Bioimaging, National Research Council (CNR-IBB), Napoli 80134, Italy. robertaiannitti@gmail.com.
Roberta
R
Iannitti
Institute of Biostructure and Bioimaging, National Research Council (CNR-IBB), Napoli 80134, Italy. annamaria.sandomenico@gmail.com.
Annamaria
A
Sandomenico
Institute of Biostructure and Bioimaging, National Research Council (CNR-IBB), Napoli 80134, Italy. menotti.ruvo@unina.it.
Menotti
M
Ruvo
Institute of Biosciences and BioResources, National Research Council (CNR-IBBR), Napoli 80131, Italy. marco.balestrieri@ibbr.cnr.it.
Marco
M
Balestrieri
Institute of Biosciences and BioResources, National Research Council (CNR-IBBR), Napoli 80131, Italy. mose.rossi@ibbr.cnr.it.
Mosè
M
Rossi
Institute of Biosciences and BioResources, National Research Council (CNR-IBBR), Napoli 80131, Italy. gianna.palmieri@ibbr.cnr.it.
Gianna
G
Palmieri
D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology; D010447:Peptide Hydrolases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism
D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D010455:Peptides; D012333:RNA, Messenger; D010447:Peptide Hydrolases; C038220:acylaminoacyl-peptidase; D046988:Proteasome Endopeptidase Complex
acylpeptide hydrolase (APEH); anti-tumoral target; osteosarcoma cell lines; peptide inhibitor; proteasome
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