The
acyl-CoA synthetase 4 (ACSL4), which esterify 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 may constitute potential therapeutic targets for the control of
tumor growth. Therefore, the aim of this study was to use a
tetracycline Tet-Off system of MCF-7 xenograft model of
breast cancer to confirm the effect of ACSL4 overexpression on
tumor growth in vivo. We also aim to determine whether a combinatorial inhibition of the ACSL4-LOX-COX-2 pathway affects
tumor growth in vivo using a xenograft model based on MDA-MB-231 cells, a highly aggressive
breast cancer cell line naturally overexpressing ACSL4. The first novel finding is that stable transfection of MCF-7 cells with ACSL4 using the
tetracycline Tet-Off system of MCF-7 cells resulted in development of growing
tumors when injected into nude mice.
Tumor xenograft development measured in animals that received
doxycycline resulted in
tumor growth inhibition. The
tumors presented marked nuclear polymorphism, high mitotic index and low expression of
estrogen and
progesterone receptor. These results demonstrate the transformational capacity of ACSL4 overexpression. We 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 proliferation as well as metastatic potential of
cancer cells.