The role of vulpinic acid as a natural compound in the regulation of breast cancer-associated miRNAs

Abstract

Background Breast cancer is the most frequently diagnosed cancer, and no effective treatment solution has yet been found. The number of studies based on the research of novel natural compounds in the treatment of breast cancer has been increasing in recent years. The anticancer properties of natural compounds are related to the regulation of microRNA (miRNA) expression. Therefore, changing the profile of miRNAs with the use of natural products is very important in cancer treatment. However, the role of vulpinic acid and related miRNAs in breast cancer progression remains unknown. Vulpinic acid, methyl (as2E)-2-(3-hydroxy-5-oxo-4-phenylfuran-2-ylidene)-2 phenylacetate, is a natural product extracted from the lichen species and shows an anticancer effect on different cancer cells. Methods This study examines the effects of vulpinic acid on the miRNA levels of breast cancer (MCF-7) cells and its relationship with cell proliferation and apoptosis levels. The antiproliferative effect of vulpinic acid was screened against MCF-7 breast cancer cells and MCF-12A breast epithelial cells using the xCELLigence real-time cell analysis system. We analyzed the altered miRNA expression profile in MCF-7 breast cancer cells versus MCF-12A cells following their response to vulpinic acid through microarray analysis. The microarray analysis results were confirmed through quantitative real-time PCR and bioinformatics analysis. Results The results of the miRNA array and bioinformatic analyses demonstrated that 12 miRNAs were specifically responsive to vulpinic acid in MCF-7 breast cancer cells. This is the first study to reveal that vulpinic acid inhibits the expression of 12 miRNAs and suppresses breast cancer cell proliferation. The study also revealed that vulpinic acid may downregulate the expression of 12 miRNAs by repressing the FOXO-3 gene. The miRNA targets were mainly found to play a role in the apoptosis, cell cycle and MAPK pathways. Moreover, Bcl-2, Bax, procaspase-3 and procaspase-9 protein levels were assessed by western blot analysis for validation of apoptosis at the protein level. Conclusion This study revealed the molecular mechanisms of vulpinic acid on breast cancer and showed that vulpinic acid regulates apoptosis signaling pathways by decreasing the expression of miRNAs. The miRNA expression patterns illuminate the underlying effect of vulpinic acid in breast cancer treatment. Graphical Abstract

The Combined Effect of Vulpinic Acid and Doxorubicin in Breast Cancer MCF-7 Cells

“…The results showed that VA significantly inhibited cell viability and induced apoptosis of human breast cancer cells while While it has no significant cytotoxic or apoptotic effects on non-cancerous cells [14]. Cansaran-Duman et al ( 2021) investigated the role of vulpinic acid (VA) on the progression of breast cancer and reported that VA could downregulate the expression of 12 miRNAs by silencing the FOXO-3 gene [20]. Another study reported that VA exhibited anti-cancer activity in the breast cancer cell lines MCF-7 and MDA-MB-453 by inhibiting Thioredoxin reductases-1 (TRXR1) enzyme, which is recognized as a cancer marker, preventing migration and inducing apoptosis [11].…”

A Review of Twenty Years of Research on the Regulation of Signaling Pathways by Natural Products in Breast Cancer

“…In the previous studies, vulpinic acid has been used for breast treatment as it induces apoptosis and suppresses Bcl-2 [ 152 ]. Cansaran-Duman et al [ 28 ] conducted an in vitro study and investigated the role of vulpinic acid on BC by regulating the expression of miRNA levels. They found that vulpinic acid induced apoptosis in MCF-7 by elevating the level of FOXO-3 and Bax, and suppressing Bcl-2 and pro-caspase-3,9, thus altering the tumor suppressor miRNAs (see Table 1 ).…”

“…Recently, various natural products have been discovered and tested as anti-BC agents. These natural products are viridiflorol, verminoside, novel phloroglucinol derivatives, genistein, vulpinic acid, calcitrinone A, kaempferol, protopanaxadiol, thymoquinone, arctigenin, glycyrrhizin, 25-OCH3-PPD, oridonin, apigenin, wogonin, fisetin, curcumin, berberine, cimigenoside, and resveratrol [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. These natural products are alkaloids, antioxidants, phenolic compounds, flavonoids, and polyphenols in nature, and are obtained from herbal products and vegetables.…”