التفاصيل البيبلوغرافية
| العنوان: |
New inhibitor targeting Acyl-CoA synthetase 4 reduces breast and prostate tumor growth, therapeutic resistance and steroidogenesis. |
| المؤلفون: |
Castillo, Ana F., Orlando, Ulises D., Maloberti, Paula M., Prada, Jesica G., Dattilo, Melina A., Solano, Angela R., Bigi, María M., Ríos Medrano, Mayra A., Torres, María T., Indo, Sebastián, Caroca, Graciela, Contreras, Hector R., Marelli, Belkis E., Salinas, Facundo J., Salvetti, Natalia R., Ortega, Hugo H., Lorenzano Menna, Pablo, Szajnman, Sergio, Gomez, Daniel E., Rodríguez, Juan B. |
| المصدر: |
Cellular & Molecular Life Sciences; Mar2021, Vol. 78 Issue 6, p2893-2910, 18p |
| مصطلحات موضوعية: |
TUMOR growth, PROSTATE tumors, BREAST tumors, NUCLEAR magnetic resonance spectroscopy, ACYL coenzyme A, EXOCRINE glands |
| مستخلص: |
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. [ABSTRACT FROM AUTHOR] |
|
Copyright of Cellular & Molecular Life Sciences is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) |
| قاعدة البيانات: |
Complementary Index |
Full Text Finder