INVESTIGADORES
DUARTE Alejandra Beatriz
artículos
Título:
Functional interaction between acyl-CoA synthetase 4, lipooxygenases and cyclooxygenase-2 in the aggressive phenotype of breast cancer cells.
Autor/es:
MALOBERTI PAULA; DUARTE ALEJANDRA; ORLANDO ULISES; PASQUALINI MARIA EUGENIA; SOLANO ANGELA R; LÓPEZ-OTIN CARLOS; PODESTÁ ERNESTO J
Revista:
PLOS ONE
Editorial:
PUBLIC LIBRARY SCIENCE
Referencias:
Año: 2010 vol. 5 p. 1 - 12
ISSN:
1932-6203
Resumen:
The acyl-CoA synthetase 4 (ACSL4) is increased in breast cancer, colon and hepatocellular carcinoma. ACSL4 mainly esterifies
arachidonic acid (AA) into arachidonoyl-CoA, reducing free AA intracellular levels, which is in contradiction with the need for
AA metabolites in tumorigenesis. Therefore, the causal role of ACSL4 is still not established. This study was undertaken to
determine the role of ACSL4 in AA metabolic pathway in breast cancer cells. The first novel finding is that ACSL4 regulates
the expression of cyclooxygenase-2 (COX-2) and the production of prostaglandin in MDA-MB-231 cells. We also found that
ACSL4 is significantly up-regulated in the highly aggressive MDA-MB-231 breast cancer cells. In terms of its overexpression
and inhibition, ACSL4 plays a causal role in the control of the aggressive phenotype. These results were confirmed by the
increase in the aggressive behaviour of MCF-7 cells stably transfected with a Tet-off ACSL4 vector. Concomitantly, another
significant finding was that intramitochondrial AA levels are significantly higher in the aggressive cells. Thus, the
esterification of AA by ACSL4 compartmentalizes the release of AA in mitochondria, a mechanism that serves to drive the
specific lipooxygenase metabolization of the fatty acid. To our knowledge, this is the first report that ACSL4 expression
controls both lipooxygenase and cyclooxygenase metabolism of AA. Thus, this functional interaction represents an
integrated system that regulates the proliferating and metastatic potential of cancer cells. Therefore, the development of
combinatory therapies that profit from the ACSL4, lipooxygenase and COX-2 synergistic action may allow for lower
medication doses and avoidance of side effects.