The functional interaction between acyl-CoA synthetase 4, 5-lipooxygenase and cyclooxygenase-2 controls tumor growth: a novel therapeutic target

ORLANDO U.; GARONA J.; RIPOLL G. V.; MALOBERTI P.; SOLANO A.; AVAGNINA A.; ALONSO D.F.; GOMEZ D.E.; PODESTÁ E.

PLOS ONE

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2012 vol. 7 p. 1 - 14

1932-6203

The acyl-CoA synthetase 4 (ACSL4), which belongs to a five-member family of enzymes that esterifies mainly arachidonic acid (AA) into acyl-CoA, is increased in breast, colon and hepatocellular carcinoma. The transfection of MCF-7 cells with ACSL4 cDNA transforms the cells into a highly aggressive phenotype and controls both lipooxygenase-5 (LOX-5) and cyclooxygenase-2 (COX-2) metabolism of AA, suggesting a causal role of ACSL4 in tumorigenesis. We hypothesized that ACSL4, LOX-5 and COX-2 could constitute potential therapeutic targets for the control of tumor growth. Therefore, the aim of this study was to use a xenograft model of breast cancer to confirm the effect of ACSL4 overexpression on tumor growth in vivo, and to determine whether a combinatorial inhibition of the ACSL4-LOX-COX-2 pathway affects tumor growth in vivo. The first novel finding is that stable transfection of ACSL4 of MCF-7 cells resulted in development of tumors when injected into nude mice. The tumors presented marked nuclear polymorphism, high mitotic index and low expression of estrogen and progesterone receptor. Tumor xenograft development measured in animals that received doxycycline resulted in tumor growth inhibition. These results demonstrated the transformational capacity of ACSL4 overexpression. We subsequently examined the effect of a combination of inhibitors of ACSL4, LOX-5 and COX-2 on MDA-MB-231 tumor xenografts. This treatment markedly reduced tumor growth in doses of these inhibitors that were otherwise ineffective when used alone, indicating a synergistic effect of the compounds. Our results suggest that these enzymes interact functionally and form an integrated system that operates in a concerted manner to regulate tumor growth and consequently may be potential therapeutic targets for the control of tumor growth as well as the proliferation and metastatic potential of cancer cells.