2. Academic Validation
  3. N-Acylethanolamine acid amidase (NAAA) is dysregulated in colorectal cancer patients and its inhibition reduces experimental cancer growth

N-Acylethanolamine acid amidase (NAAA) is dysregulated in colorectal cancer patients and its inhibition reduces experimental cancer growth

  • Br J Pharmacol. 2022 Apr;179(8):1679-1694. doi: 10.1111/bph.15737.
Barbara Romano 1 2,  Ester Pagano 1 2,  Fabio A Iannotti 2 3,  Fabiana Piscitelli 2 3,  Vincenzo Brancaleone 4,  Giuseppe Lucariello 1,  Maria Francesca Nanì 1 2,  Ferdinando Fiorino 1,  Rosa Sparaco 1,  Giovanna Vanacore 1,  Federica Di Tella 1,  Donatella Cicia 1,  Ruggero Lionetti 5,  Alexandros Makriyannis 6,  Michael Malamas 6,  Marcello De Luca 5,  Giovanni Aprea 7,  Maria D'Armiento 8,  Raffaele Capasso 2 9,  Bernardo Sbarro 1,  Tommaso Venneri 1 2,  Vincenzo Di Marzo 2 3 10 11,  Francesca Borrelli 1 2,  Angelo A Izzo 1 2
Affiliations

Affiliations

  • 1 Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy.
  • 2 Endocannabinoid Research Group, Pozzuoli, Italy.
  • 3 Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy.
  • 4 Department of Science, University of Basilicata, Potenza, Italy.
  • 5 Department of Public Health, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy.
  • 6 Center for Drug Discovery and Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts, USA.
  • 7 Department of Clinical Medicine and Surgery, Interuniversity Center for Technological Innovation Interdepartmental Center for Robotic Surgery, University of Naples Federico II, Naples, Italy.
  • 8 Department of Biomorphological and Functional Science, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy.
  • 9 Department of Agricultural Sciences, University of Naples Federico II, Naples, Italy.
  • 10 Centre de Recherche de l'Institut Universitaire de Cardiologie et Pneumologie de Quèbec, Quebec City, Quebec, Canada.
  • 11 Institut sur la Nutrition et les Aliments Fonctionnels, Université Laval, Quebec City, Quebec, Canada.
PMID: 34791641 DOI: 10.1111/bph.15737
Abstract

Background and purpose: N-Acylethanolamine acid amidase (NAAA) is a lysosomal enzyme accountable for the breakdown of N-acylethanolamines (NAEs) and its pharmacological inhibition has beneficial effects in inflammatory conditions. The knowledge of NAAA in Cancer is fragmentary with an unclarified mechanism, whereas its contribution to colorectal Cancer (CRC) is unknown to date.

Experimental approach: CRC xenograft and azoxymethane models were used to assess the in vivo effect of NAAA inhibition. Further, the tumour secretome was evaluated by an oncogenic array, CRC cell lines were used for in vitro studies, cell cycle was analysed by cytofluorimetry, NAAA was knocked down with siRNA, human biopsies were obtained from surgically resected CRC patients, gene expression was measured by RT-PCR and NAEs were measured by LC-MS.

Key results: The NAAA inhibitor AM9053 reduced CRC xenograft tumour growth and counteracted tumour development in the azoxymethane model. NAAA inhibition affected the composition of the tumour secretome inhibiting the expression of EGF family members. In CRC cells, AM9053 reduced proliferation with a mechanism mediated by PPAR-α and TRPV1. AM9053 induced cell cycle arrest in the S phase associated with cyclin A2/CDK2 down-regulation. NAAA knock-down mirrored the effects of NAAA inhibition with AM9053. NAAA expression was down-regulated in human CRC tissues, with a consequential augmentation of NAE levels and dysregulation of some of their targets.

Conclusion and implications: Our results show novel data on the functional importance of NAAA in CRC progression and the mechanism involved. We propose that this enzyme is a valid drug target for the treatment of CRC growth and development.

Keywords

acylethanolamides; colon cancer; endocannabinoid system.

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