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

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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.

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Fig. 1

taken from the 817 breast tumor samples in TGCA dataset. TN, triple-negative breast tumors; LumB, invasive ductal cancer luminal B subtype; LumA, invasive ductal cancer luminal A subtype; ILC-LumA: invasive lobular cancer luminal A; ILC: invasive lobular cancer; All, all samples

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Availability of data and materials

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.

Abbreviations

ACSL4:

Acyl-CoA synthetase 4

ER:

Estrogen receptor

PR:

Progesterone receptors

HER2:

Epidermal growth factor-2 receptor

AR:

Androgen receptor

StAR:

Steroidogenic acute regulatory protein

D-MEM:

Dulbecco’s modified Eagle medium

FCS:

Fetal calf serum

MTT:

3-(4, 5-Dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazoliumbromide)

BrdU:

5-Bromo-2′-deoxyuridine

hCG:

Human chorionic gonadotropin

[3H]-AA:

Arachidonic Acid [5, 6, 8, 9, 11, 12, 14, 15-3H (N)]

NMR:

Nuclear magnetic resonance

MS:

High-resolution mass spectra

HRMS-ESI:

High resolution electrospray ionization mass spectrometry

RPMI:

Roswell Park Memorial Institute media

HS:

Horse serum

RIA:

Radioimmunoassay

i.p.:

Intraperitoneal

BSA:

Bovine serum albumin

DAPI:

4′, 6-Diamidino-2-phenylindole

CAM:

Chick embryo chorioallantoic membrane assay

IHC:

Immunohistochemistry

ANOVA:

Analysis of variance

RPPA:

Reverse-phase protein array

AA-CoA:

Arachidonoyl-CoA

AA:

Arachidonic acid

LH:

Luteinizing hormone

ACTH :

Adrenocorticotropic hormone

4-OHTAM:

4-Hydroxytamoxifen

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Acknowledgments

We thank Lucía M. Herrera and Nadin Calvente for technical support. We thank María M. Rancez for providing language help and writing assistance.

Funding

This work was supported by National Scientific and Technical Research Council (CONICET) – Argentina, P.U.E (2016–2021, 22920160100062, Podesta, https://www.conicet.gov.ar), University of Buenos Aires – Argentina (UBACYT 2017–2019, 20020160100099BA, Maloberti; UBACYT 2018–2019, 20020170200347BA, Castillo; https://www.uba.ar/secyt/), National Agency for Scientific and Technological Promotion, MinCyT – Argentina (PICT 2016–0418, Orlando; PICT 2015–3561, Castillo; PICT 2014–0972, Maloberti; https://www.agencia.mincyt.gob.ar/.

Author information

Author notes

  1. Ana F. Castillo, Ulises D. Orlando and Paula M. Maloberti these authors contributed equally.

Authors and Affiliations

  1. Instituto de Investigaciones Biomédicas (INBIOMED), CONICET, Universidad de Buenos Aires, Paraguay 2155 (C1121ABG), Buenos Aires, Argentina

    Ana F. Castillo, Ulises D. Orlando, Paula M. Maloberti, Jesica G. Prada, Melina A. Dattilo, Angela R. Solano, María M. Bigi, Mayra A. Ríos Medrano & Ernesto J. Podesta

  2. Departamento de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina

    Ana F. Castillo, Ulises D. Orlando, Paula M. Maloberti, Jesica G. Prada, Melina A. Dattilo, Angela R. Solano, María M. Bigi, Mayra A. Ríos Medrano & Ernesto J. Podesta

  3. Departamento de Oncología Básico Clínico, Facultad de Medicina, Universidad de Chile, Santiago, Chile

    María T. Torres, Sebastián Indo, Graciela Caroca & Hector R. Contreras

  4. Instituto de Ciencias Veterinarias del Litoral (ICiVet-Litoral), CONICET, Universidad Nacional del Litoral, Esperanza, Santa Fe, Argentina

    Belkis E. Marelli, Facundo J. Salinas, Natalia R. Salvetti & Hugo H. Ortega

  5. Laboratorio de Oncología Molecular, Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes, Bernal, Provincia de Buenos Aires, Argentina

    Pablo Lorenzano Menna & Daniel E. Gomez

  6. Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina

    Sergio Szajnman & Juan B. Rodríguez

  7. Unidad de Microanálisis y Métodos Físicos Aplicados a Química Orgánica (UMYMFOR), CONICET, Universidad de Buenos Aires, Buenos Aires, Argentina

    Sergio Szajnman & Juan B. Rodríguez

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Contributions

AFC, UDO, PMM, conceptualized, designed and performed research; JGP, MAD, ARS, MMB, MARM, SS, PLM, MTT, SI, GC, HRC, BEM, FJS, NRS, HHO performed research; DEG, JBR conceptualized and performed research; EJP. conceptualized research; AFC, UDO, PMM, EJP analyzed data and wrote the paper.

Corresponding author

Correspondence to Ernesto J. Podesta.

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The authors have declared that no competing interest exists. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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All procedures were approved by the Ethics and Animal Welfare Committee according to the Standardized Operational Procedures of the Center for Comparative Medicine at Instituto de Ciencias Veterinarias del Litoral (ICIVET-Litoral) and by the Ethics and Safety Committee at the School of Veterinary Sciences, Universidad Nacional del Litoral. All human procedures are conformed to the guidelines of the World Medical Assembly (Declaration of Helsinki) and were approved by the Ethics Committee for Research on Human Beings and the Risk Prevention and Biosafety Unit at the School of Medicine, Universidad de Chile, and the Ethics and Research Committee of the Clinical Hospital, Universidad de Chile. In all cases, informed consent was obtained from each patient.

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Castillo, A.F., Orlando, U.D., Maloberti, P.M. et al. New inhibitor targeting Acyl-CoA synthetase 4 reduces breast and prostate tumor growth, therapeutic resistance and steroidogenesis. Cell. Mol. Life Sci. 78, 2893–2910 (2021). https://doi.org/10.1007/s00018-020-03679-5

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