Abstract
Existing therapeutic strategies for breast cancer are limited by tumor recurrence and drug-resistance. Antioxidant plant-derived compounds such as flavonoids reduce adverse outcomes and have been identified as a potential source of antineoplastic agent with less undesirable side effects. Here, we describe the novel regulation of fatty-acid synthase (FASN), the key enzyme in de novo fatty-acid synthesis, whereby Vitis vinifera L. cv Vermentino leaf hydroalcoholic extract lowers its protein stability that is regulated by small ubiquitin-like modifier (SUMO)ylation. The phenolic compounds characterization was performed by liquid chromatography–mass spectrometry (LC–MS), whereas mass spectrometry (LC–MS/MS), Western blotting/co-immunoprecipitation (Co-IP) and RT-PCR, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), clonogenicity assays, and FACS analysis were used to measure the expression of targets and tumorigenicity. Vermentino extract exhibits antitumorigenic effects, and we went on to determine that FASN and ubiquitin-conjugating enzyme 9 (UBC9), the sole E2 enzyme required for SUMOylation, were significantly reduced. Moreover, FASN was found SUMOylated in human breast cancer tissues and cell lines, and lack of SUMOylation caused by SUMO2 silencing reduced FASN protein stability. These results suggest that SUMOylation protects FASN against proteasomal degradation and may exert oncogenic activity through alteration of lipid metabolism, whereas Vermentino extract inhibits these effects which supports the additional validation of the therapeutic value of this compound in breast cancer.
Highlights
Breast cancer is the most common malignant cancer in females worldwide [1]
The human breast cancer cell lines MCF-7 and SKBR-3 as well as the MCF-12A normal breast epithelial cell line were obtained from the American Type Culture Collection (ATCC, Rockville, MD, USA) and were grown according to instructions provided by the ATCC
Vermentino compound showed significant cytotoxic activity at each concentration, with a 50% reduction of viability following treatment of MCF-7 and SKBR-3 cell lines with 400 μg/mL of the hydroalcoholic extract compared to the control (Figure 1A)
Summary
The existing therapeutic strategies for breast cancer, which include surgery, endocrine therapy, and chemotherapy, are limited by tumor recurrence and drug resistance [2]. Adjuvant therapies often attempt to induce cytotoxicity in tumor cells. As tumor cells are known to rely on alternate metabolic processes, such as de novo fatty-acid synthesis, these pathways harbor many potential therapeutic targets. Inhibition of fatty-acid synthesis promotes apoptosis and produces cytotoxicity, which can trigger cell death [3]. FASN catalyzes acetyl coenzyme A (CoA) and malonyl-Co to form palmitate and a 16-carbon fatty acid [4]. FASN is highly expressed in various breast cancer cell lines, including hormone-independent lines, such as SKBR-3, and hormone dependent lines, such as MCF-7 [5]. AKT1 activation protects cells from cell death following inhibition of fatty-acid synthesis [7]
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