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 IC50 of 2.3 μM in both
MDA-MB-468 and MDA-MB-231 cells, while in 3D spheroids, the IC50 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.
