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Selective inhibition of acylpeptide hydrolase in SAOS-2 osteosarcoma cells: is this enzyme a viable anticancer target?

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Abstract

Serine hydrolases play crucial roles in many physiological and pathophysiological processes and a panel of these enzymes are targets of approved drugs. Despite this, most of the human serine hydrolases remain poorly characterized with respect to their biological functions and substrates and only a limited number of in vivo active inhibitors have been so far identified. Acylpeptide hydrolase (APEH) is a member of the prolyl-oligopeptidase class, with a unique substrate specificity, that has been suggested to have a potential oncogenic role. In this study, a set of peptides was rationally designed from the lead compound SsCEI 4 and in vitro screened for APEH inhibition. Out of these molecules, a dodecapeptide named Ala 3 showed the best inhibitory effects and it was chosen as a candidate for investigating the anti-cancer effects induced by inhibition of APEH in SAOS-2 cell lines. The results clearly demonstrated that Ala 3 markedly reduced cell viability via deregulation of the APEH-proteasome system. Furthermore, flow cytometric analysis revealed that Ala 3 anti-proliferative effects were closely related to the activation of a caspase-dependent apoptotic pathway. Our findings provide further evidence that APEH can play a crucial role in the pathogenesis of cancer, shedding new light on the great potential of this enzyme as an attractive target for the diagnosis and the quest for selective cancer therapies.

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Acknowledgements

The authors would like to thank Dr. Giovanni Del Monaco for his assistance with statistical analysis.

Funding

This research was supported by Regione Campania—“PREMIO-Infrastruttura per la Medicina di Precisione in Oncologia”. Manifestazione di interesse per la realizzazione di progetti di sviluppo/potenziamento di infrastrutture di ricerca strategica regionali per la lotta alle patologie oncologiche (RIS3)-POR CAMPANIA FESR 2014/2020. This work was partially supported by the Association Impegno per la Vita -Onlus, Pozzuoli, Napoli, Italy and by the CNR Project NUTR-AGE (FOE-2019, DSB.AD004.271).

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Authors and Affiliations

  1. Institute of Biosciences and BioResources, National Research Council (CNR-IBBR), 80131, Napoli, Italy

    Marta Gogliettino, Ennio Cocca, Lorena Gratino, Mosè Rossi & Gianna Palmieri

  2. Institute of Biostructure and Bioimaging, National Research Council (CNR-IBB), 80134, Napoli, Italy

    Annamaria Sandomenico, Emanuela Iaccarino & Luisa Calvanese

Authors
  1. Marta Gogliettino
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  2. Ennio Cocca
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  6. Luisa Calvanese
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  7. Mosè Rossi
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  8. Gianna Palmieri
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Contributions

Conceptualization: GP; Methodology: EC, AS, LG, EI, LC; Formal analysis and investigation: MG, EC, GP; Writing-original draft preparation: MG, GP; Writing—review and editing: MG, EC, MR, GP; Funding acquisition: MR; Resources: GP; Supervision: MR, GP. All authors provided critical feedback and helped shape the research, analysis and manuscript.

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Correspondence to Gianna Palmieri.

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Gogliettino, M., Cocca, E., Sandomenico, A. et al. Selective inhibition of acylpeptide hydrolase in SAOS-2 osteosarcoma cells: is this enzyme a viable anticancer target?. Mol Biol Rep 48, 1505–1519 (2021). https://doi.org/10.1007/s11033-020-06129-4

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