Beauvericin Reverses Epithelial-to-Mesenchymal Transition in Triple-Negative Breast Cancer Cells through Regulation of Notch Signaling and Autophagy.

Metastasis stands as a prime contributor to triple-negative breast cancer (TNBC) associated mortality worldwide, presenting heightened severity and significant challenges due to limited treatment options. Addressing TNBC metastasis necessitates innovative approaches and novel therapeutics to specifically target its propensity for dissemination to distant organs. Targeted therapies capable of reversing epithelial-to-mesenchymal transition (EMT) play a crucial role in suppressing metastasis and enhancing the treatment response. Beauvericin, a promising fungal secondary metabolite, exhibits significant potential in diminishing the viability of EMT-induced TNBC cells by triggering intracellular oxidative stress, as evidenced by an enhanced reactive oxygen species level and reduced mitochondrial transmembrane potential. In monolayer cultures, it has exhibited an IC ₅₀ of 2.3 μM in both MDA-MB-468 and MDA-MB-231 cells, while in 3D spheroids, the IC ₅₀ values are 9.7 and 7.1 μM, respectively. Beauvericin has also reduced the migratory capability of MDA-MB-468 and MDA-MB-231 cells by 1.5- and 1.7-fold, respectively. Both qRT-PCR and Western blot analysis have shown significant upregulation in the expression of epithelial marker (E-cadherin) and downregulation in the expression of mesenchymal markers (N-cadherin, vimentin, Snail, Slug, and β-catenin), following treatment, indicating reversal of EMT. Furthermore, beauvericin has suppressed the Notch signaling pathway by substantially downregulating Notch-1, Notch-3, Hes-1, and cyclinD3 expression and induced autophagy as observed by elevated expression of autophagy markers LC3 and Beclin-1. In conclusion, beauvericin has successfully downregulated TNBC cell survival by inducing oxidative stress and suppressed their migratory potential by reversing EMT through the inhibition of Notch signaling and activation of autophagy.
Competing Interests: The authors declare no competing financial interest.
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