2. Academic Validation
  3. New inhibitor targeting Acyl-CoA synthetase 4 reduces breast and prostate tumor growth, therapeutic resistance and steroidogenesis

New inhibitor targeting Acyl-CoA synthetase 4 reduces breast and prostate tumor growth, therapeutic resistance and steroidogenesis

  • Cell Mol Life Sci. 2021 Mar;78(6):2893-2910. doi: 10.1007/s00018-020-03679-5.
Ana F Castillo  # 1 2,  Ulises D Orlando  # 1 2,  Paula M Maloberti  # 1 2,  Jesica G Prada 1 2,  Melina A Dattilo 1 2,  Angela R Solano 1 2,  María M Bigi 1 2,  Mayra A Ríos Medrano 1 2,  María T Torres 3,  Sebastián Indo 3,  Graciela Caroca 3,  Hector R Contreras 3,  Belkis E Marelli 4,  Facundo J Salinas 4,  Natalia R Salvetti 4,  Hugo H Ortega 4,  Pablo Lorenzano Menna 5,  Sergio Szajnman 6 7,  Daniel E Gomez 5,  Juan B Rodríguez 6 7,  Ernesto J Podesta 8 9
Affiliations

Affiliations

  • 1 Instituto de Investigaciones Biomédicas (INBIOMED), CONICET, Universidad de Buenos Aires, Paraguay 2155 (C1121ABG), Buenos Aires, Argentina.
  • 2 Departamento de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
  • 3 Departamento de Oncología Básico Clínico, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
  • 4 Instituto de Ciencias Veterinarias del Litoral (ICiVet-Litoral), CONICET, Universidad Nacional del Litoral, Esperanza, Santa Fe, Argentina.
  • 5 Laboratorio de Oncología Molecular, Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes, Bernal, Provincia de Buenos Aires, Argentina.
  • 6 Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.
  • 7 Unidad de Microanálisis y Métodos Físicos Aplicados a Química Orgánica (UMYMFOR), CONICET, Universidad de Buenos Aires, Buenos Aires, Argentina.
  • 8 Instituto de Investigaciones Biomédicas (INBIOMED), CONICET, Universidad de Buenos Aires, Paraguay 2155 (C1121ABG), Buenos Aires, Argentina. ernestopodesta@yahoo.com.ar.
  • 9 Departamento de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina. ernestopodesta@yahoo.com.ar.
  • # Contributed equally.
PMID: 33068124 DOI: 10.1007/s00018-020-03679-5
Abstract

Acyl-CoA synthetase 4 (ACSL4) is an isoenzyme of the fatty acid ligase-coenzyme-A family taking part in arachidonic acid metabolism and steroidogenesis. ACSL4 is involved in the development of tumor aggressiveness in breast and prostate tumors through the regulation of various signal transduction pathways. Here, a bioinformatics analysis shows that the ACSL4 gene expression and proteomic signatures obtained using a cell model was also observed in tumor samples from breast and Cancer patients. A well-validated ACSL4 inhibitor, however, has not been reported hindering the full exploration of this promising target and its therapeutic application on Cancer and steroidogenesis inhibition. In this study, ACSL4 inhibitor PRGL493 was identified using a homology model for ACSL4 and docking based virtual screening. PRGL493 was then chemically characterized through nuclear magnetic resonance and mass spectroscopy. The inhibitory activity was demonstrated through the inhibition of arachidonic acid transformation into arachidonoyl-CoA using the recombinant Enzyme and cellular models. The compound blocked cell proliferation and tumor growth in both breast and prostate cellular and animal models and sensitized tumor cells to chemotherapeutic and hormonal treatment. Moreover, PGRL493 inhibited de novo steroid synthesis in testis and adrenal cells, in a mouse model and in prostate tumor cells. This work provides proof of concept for the potential application of PGRL493 in clinical practice. Also, these findings may prove key to therapies aiming at the control of tumor growth and drug resistance in tumors which express ACSL4 and depend on steroid synthesis.

Keywords

Anti-hormone treatment resistance; Castration resistant prostate cancer; Chemotherapy resistance; Triple negative breast cancer.

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