Abstract
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.
Highlights
Breast cancer is the most frequent malignant disease in women and the second leading cause of cancer-related deaths in the U.S, affecting one in eight Americans throughout their lifetime [1]
We previously demonstrated that overexpression of ACSL4 results in a significant increase in the proliferation and invasion rate of MCF-7 cells compared to mock-transfected cells [21]
Tumors were significantly larger in animals inoculated with MCF-7 TetOff/ACSL4 cells compared to the mass observed when animals were inoculated with MCF-7 Tet-Off empty vector cells analyzed by two-way ANOVA (Figure 1A)
Summary
Breast cancer is the most frequent malignant disease in women and the second leading cause of cancer-related deaths in the U.S, affecting one in eight Americans throughout their lifetime [1]. Mechanisms involved in the frequent failure of chemotherapy, endocrine therapy or immunotherapy to successfully treat breast cancer are elusive and are being investigated. Random mutation events and/or epigenetic changes of cancer cells followed by the selection of more malignant variants or the acquisition of stem cell-like properties are thought to be the mechanism for tumor progression and for the generation of a heterogeneous tumor cell population [3,4]. Cancer is a disease with genomic perturbation that leads to dysregulation of multiple pathways within the cellular system. Of these pathways, alterations in arachidonic acid (AA) metabolism have been suggested to contribute to tumorigenesis and tumor progression [5,6,7,8]. The direct impact of this knowledge on tumor treatment and prevention is still largely unproven
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